Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. nelui-1 h icy yoiei namto n therapy Datsi and Angeliki inflammation in cytokine ‘itchy’ The Interleukin-31: neiiDatsi Angeliki therapy and title: inflammation Running in cytokine ‘itchy’ The Interleukin-31: Review type: 0000-0002-2394-3269) Article ID: (ORCID PhD MD, Buddenkotte, 0000-0002-7090-2187) Joerg ID: (ORCID PhD MD, Steinhoff, Martin 0000-0003-2827-8744) ID: (ORCID PhD Ahmad, Fareed 0000-0002-5783-6605) ID: (ORCID PhD Alam, Majid 0000-0001-5022-8087) ID: future. (ORCID the PhD in disorders Datsi, pruritic Angeliki and whether neuroinflammatory example, inflammatory, For for approach IL-31/IL31RA/OSMR nodularis. promising the Targeting prurigo a downstream clarified. including be IL-31 be to diseases of to appears inflammatory needs inhibition involved axis IL-31-mediated-signaling various Accordingly, cytokine block for directly antibody. critical approach inhibitors including anti-IL-31 a JAK beneficial diseases an downstream is a neuroinflammatory using IL-31 in be trials may modulation clinical cells. recent cytokine signaling immune by for innate avenues validated various new as as AD/pruritus, opens well which communication, as neuro-immune IL-31 keratinocytes in receptor including heterodimer cells the epithelial of receptor initiating activation neurons, responses, M through inflammatory (IL31RA)/Oncostatin outgrowth mediating role neuronal thereby alpha central IL-31, and a receptor play including itch Here, cells cytokines stimulating pruritus. TH2 TH2-produced and symptom diseases. of cardinal circuits, allergic levels its immunoregulatory and high of inflammatory rhinitis ‘drivers’ release modulates main (AD), and IL-31 the AD dermatitis which of by in atopic one mechanisms as as the identified such summarize to been disorders aim has atopic we IL-31 multiple AD, of In pathophysiology hyperreactivity. airway the and in implicated been has Interleukin-31 Abstract 2020 27, November 3 2 1 4 tar; D 1 Affiliations Buddenkotte emtlg nttt,Aaei elhSse,HmdMdclCroain oa Qatar; D Doha, Corporation, Hospital Medical Hamad University System, Health Academic Therapeutics, Institute, Dermatology Cell and Diagnostics Transplantational for Institute el onl eiieQatar Medicine Cornell Weill Corporation Medical Hamad Duesseldorf Universittaetsklinikum sedr,Germany; usseldorf, ¨ 3 rnltoa eerhIsiue cdmcHat ytm aa eia oprto,Dh,Qatar; Doha, Corporation, Medical Hamad System, Health Academic Institute, Research Translational 2,3,* 1 nelui-1i namto n allergy and inflammation in Interleukin-31 1 ai Alam Majid , ai Alam Majid , 2 eateto emtlg n eeelg,HmdMdclCroain oa Qa- Doha, Corporation, Medical Hamad Venereology, and Dermatology of Department 2 aedAhmad Fareed , 2,3 aedAhmad Fareed , β. L1Aepeso sfudo ua n uiedra otganglia root dorsal murine and human on found is expression IL31RA 1 2 atnSteinhoff Martin , 2,3 atnSteinhoff Martin , 3 n or Buddenkotte Joerg and , 2-7* n Joerg and , 5 Department usseldorf, ¨ 2 β Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. hmcsrmllmhpitn 1S2rcpo,Itrekn1rcpo-ie1 c,tp CD8 1 TSLP, type 1; Tc1, receptor 1; vanilloid receptor-like TRP 1 TRPV1, Interleukin receptor, 1; T1/ST2 receptor ankyrin lymphopoietin; transducer stromal TRP signal TRPA1, thymic STAT, potential; receptor signaling; TGF- chemokine; transient cytokine mitogen- activation-regulated beta??T and of p38 factor thymus- suppressor TARC, p38, growth transcription; SOCS, part; of activator 2/3; Pt, and Rating homolog receptor; Numerical decapentaplegic recognition pruritus against peak pattern SA, ppNRS, PRR, kinase; reaction; protein OSMR NP, 3-kinase; chain activated M; factor; polymerase phosphoinositide oncostatin growth PCR, PI3K, OSM, nerve placebo; Scale; Scale; NGF, PbO, Rating T-cells; beta; Numeric activated receptor Carried NRS, of M Observation neuropoietin; factor of NPN, Last target nuclear polyps; LOCF, NFAT1, mammalian nasal available; mTOR, factor; janus Imputation; not JAK, inhibitory Multiple NA, leukemia MI, receptor-??? rapamycin; kinase; LIF, IL-31 protein kinase; IL31RA, Mitogen-activated Investiga- MAPK, interleukin; N-terminal Forward; IGA, IL, c-Jun disease; G; JNK, bowel immunoglobulin inflammatory kinase; IgG, IBD, Severity Assessment; mites; Global Area dust tor’s Eczema house GRO- EASI, HDM, kinase; ganglion; antigen-DR; signal-regulated histocompatibility root extracellular dendri- dorsal ERK, DC, DRG, factor; ligand; CT-1, oncogene- Index; growth factor; motif) Quality endothelial inhibitory (C-X-C Life EGF, chemokine ciliary Index; Dermatology CXCL, CNTF, DLQI, CDK6, ligand; antigen; homolog; cell; motif) lymphocyte 2 tic protein (C-C cutaneous cycle chemokine CLA, division CCL, 6; cell cardiotropin-1; kinase CDC2, motif) disease; protein (C-C chemokine Crohn’s division CCL, or cell; cell differentiation presenting of antigen manuscript. APC, cluster the B; CD, revised Kinase ligand; protein critically AKT, F.A. event; adverse and AE, tivity; M.A. review. the wrote Abbreviations: and conceptualized J.B. and BioRender.com. M.S. using A.D., figures the of preparation the contribution in Author assisting for Haroon Javeria J.B.). thank We and M.S. (to National Qatar (IRGC-04-SI- Qatar Corporation, Competition Medical the Grand Acknowledgements Hamad Research of Fund, Internal MRC the (NPRP11S-0117-180326) the and Program of Foundation, 17-151) Qatar Research of Priorities Member Fund, National Research the by Supported Funding MSteinhoff@hamad.qa Qatar and In- Doha, [email protected] Research Corporation, Translational Email: Medical and Hamad Corporation System, Medical Health Hamad Academic Venereology, stitute, and PhD Dermatology MD, of Steinhoff, Department Martin & PhD MD, Buddenkotte, Joerg authors Corresponding * References: Keywords: tables: and Figures count: word Abstract count: word text Review title: running Short Qatar; Doha, Qatar; Medicine-Qatar, Cornell Weill Dermatology, of 7 eateto emtlg,WilCrelMdcn,NwYr,USA York, New Medicine, Cornell Weill Dermatology, of Department α D,Fo n rgAmnsrto;g,gyorti;GT atonetnltat HLA-DR, tract; gastrointestinal GIT, glycoprotein; gp, Administration; Drug and Food FDA, ? 5/5 97/200 A,atraieyatvtdmcohg;A,aoi emtts H,ara hyperreac- airway AHR, dermatitis; atopic AD, macrophage; activated alternatively AAM, H al/ grs4ttl(0max) (10 total figures/4 table/3 1 8caatr ( characters 38 eprcl;TR ollk eetr TNF receptor; like toll TLR, cell; helper T , 199/250 8840 nticuigasrc,fiuelgns references) legends, figure abstract, including (not 4878/4500 tpyoocsaureus; Staphylococcus < 0characters) 50 E,sahlcca neoois MD/,mothers SMAD2/3, enterotoxins; staphylococcal SEB, 2 6 aa nvriy olg fMdcn,Doha, Medicine, of College University, Qatar α ?uo erssfco lh;TRP, alpha; factor necrosis ??tumor α, β ?transforming ?? β ? oncostatin ??? growth-related + cells; T Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. dies fiscria ypo rrts ee eamt umrz h ehnssb hc IL-31 which main by the mechanisms of the one summarize as to identified aim been we has Here, T der- IL-31 diseases. atopic T pruritus. allergic AD, as and symptom such In inflammatory disorders cardinal modulates hyperreactivity. atopic its multiple airway of of and ‘drivers’ pathophysiology rhinitis the (AD), in matitis implicated been has Interleukin-31 Abstract factor; CD8 growth 2 type Tc2, h rtmjrrl fI-1wsdsrbdi nidcdmuemdlo tpcdraii (AD), dermatitis atopic of genetically was model IL-31 mouse when induced pruritus with an along in inflammation receptor described cutaneous M (IL31RA)/Oncostatin was cause to IL-31 reported of overexpressed. was role it where major first The function and structure IL-31 Introduction the in flammation. disorders pruritic words: and Key neuroinflammatory inflammatory, for in- approach IL-31/IL31RA/OSMR JAK the promising Targeting downstream a future. clarified. be whether be to example, approach to For appears beneficial needs axis a nodularis. IL-31-mediated-signaling be block prurigo may directly including signaling hibitors diseases using downstream trials inflammatory IL-31 cytokine clinical various cells. of recent for immune inhibition for avenues by Accordingly, validated innate new antibody. as various opens anti-IL-31 AD/pruritus, which as an including communication, well diseases neuro-immune as neuroinflammatory in involved in keratinocytes cytokine modulation including critical cells a epithelial is IL-31 neurons, receptor ganglia heterodimer the root receptor of dorsal activation M through (IL31RA)/Oncostatin outgrowth alpha neuronal receptor and IL-31 itch stimulating and circuits, ulatory L3 a enietfida ertr rdc fT of product (IBD), secretory disease a bowel humans as in identified inflammatory IL-31 been AD, for has role (AHR). including IL-31 hyperreactivity major disorders, airway a and Recently, inflammatory (NP) various understood. polyposis fully in differentiation. nasal not described and still proliferation been is survival, IL-31 has cell of including cooperate. function processes physiological to cellular The various subunits through of receptor signaling induction by both inducible the not needs to is but leads activity MAPK alone least non- at IL31RA a detected. note, resuming the Of been isoform has 1). short (Figure the isoform pathways with long MAPK-JNK/p38 IL31RA/OSMR isoform, the short the only a with rodents, or IL-31 long In neuronal a and function. either epithelial inhibitory forms in IL31RA observed signaling humans, predominantly In is expression types. subunit cell of IL31RA composed while is body, OSMR that mammalian The complex the family IL-31. heterodimer and a IL-6 (OSM) gp130. with M IL-31, is interacts Family OSMR oncostatin typically rather from and one but IL31RA Apart which cytokines. subunit itself, of gp130-like gp130 subunits of the IL-31. with two engage family and of not composed (OSM) gp130/IL-6 does receptor IL-31 M cardiotropin-1 the heterodimeric (CNTF), a oncostatin as factor through (LIF), inhibitory signal to cytokines ciliary factor referred (NPN), inhibitory neuropoietin often leukemia IL-27, is (CT-1), IL-21, IL-11, family subunit IL-6, receptor cytokine are gp130 clustered in members IL-6 commonly engaging are pathway The signaling cytokines shared family a Interleukin-6 activation. and character cytokines. pro-inflammatory IL-6-derived their of on based family the to belongs pruritus. IL-31 and circuits neuroimmune defence, immune mation, H -rdcdctknsicuigI-1 hrb eitn namtr epne,iiitn immunoreg- initiating responses, inflammatory mediating thereby IL-31, including cytokines 2-produced nelui-1 nelui-1rcpo ,Ocsai eetr tpcdraii,neuroin- dermatitis, atopic receptor, M Oncostatin A, receptor Interleukin-31 Interleukin-31, 1 Δ, vrsneti bevto,I-1adisrsetv eetrhtrdmrI-1receptor-A IL-31 heterodimer receptor respective its and IL-31 observation, this since Ever + change. el;U,ucrtv oii;VS iulAao cl;VG,vsua endothelial vascular VEGF, Scale; Analog Visual VAS, colitis; ulcerative UC, cells; T β eeoie ntae ciaino aoia A/TT K/IKand AKT/PI3K JAK/STAT, canonical of activation initiates heterodimer β (OSMR β. β β 1 aebe tde o hi oei isehmotss inflam- homeostasis, tissue in role their for studied been have ) uui swdl xrse hogottevroscl ye of types cell various the throughout expressed widely is subunit hsrcpo eeoie satvtdwt iia ffiiisby affinities similar with activated is heterodimer receptor This H el lyacnrlrl nA n ees ihlvl of levels high release and AD in role central a play cells 2 3 H β. el n mauednrtccls(iDC), cells dendritic immature and cells 2 L1Aepeso sfudo ua n murine and human on found is expression IL31RA 4 ciaino L3 inln pathways signaling IL-31 of Activation 3 naeeto S or OSM of Engagement 5 n ac- and β 2 Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. CD4 rngncmuemdldmntae htoeepeso fI-1i nuht ntaeasvr AD-like severe AD. a initiate of to ‘drivers’ enough molecular is major IL-31 the lesions. the of skin on overexpression being AD-like that dependent pruritic IL-13 demonstrated cause respectively, and to model activators, IL-4 sufficient mouse at is or transgenic TSLP) points sensitizers or knowledge IL-31 pruritic current IL-18, as IL-13, IL-4, act for to found concentration. been have pathophysiology. dermatitis Cytokines atopic including of pruritogens characteristics diverse all of pruritus, and transmission on signal expressed pruritic are T correct between (TRPA1) the 1 for receptor ankyrin essential IL-31. TRP are activated and oil neurons mustard DRG and identified. (TRPV1) been 1 have networks receptor stimulating interaction vanilloid keratinocytes. by and neuroinflammation from channels mediated release receptors, cells (ET-1) gnate skin endothelin-1 and and neurons chemokine DRG cytokine, murine neu- from IL-31. inducing by release thereby induced (BNP) skin sys- also the peptide nervous be into central can neuropeptides the which release to inflammation, and signal rogenic activated spinothalamicus. pain become tractus or branches contralateral itch nerve and the neighbouring cord transmit spinal nerves the exogenous cancer. the via or IL31RA, or tem like endogenous diseases diseases. various endings, metabolic systemic nerve by allergies, activated or sensory as on allergies become intractable such inflammation, dermis during and disorders being factors epidermis systemic into trigger the or develop in diseases can endings skin which nerve in (itch) Peripheral seen pruritus as induce nature, can by cytokines including mediators Multiple communication neuro-immune in poor. IL-31 very is TSLP role or pivotal IL-13 a T and (T have cells within to IL-4-expressing subpopulation found to distinct 1). was restricted expression (Figure (SOCS), is cytokine expression signaling IL-31 of IL-31 cytokine of parallel suspect’ ‘uncontrolled’ of ‘usual of in suppressor a suppression of which and in NFAT2 family signaling and NFAT1 protein IL-4 calcium-dependent the of regulators, autocrine control by under is phenotype cells their expression. maintain IL-31 and supports alone microenvironment TGF- might on the relying effect not This TGF- are and parison, molecules. IL-4 SMAD2/3 with TGF- co-stimulation simultaneous of by phosphorylation T initiated via differentiated is secretion fully IL-31 why on explain effect damping rather CD3 by T human humans and stud- Several mice in understood. CD3 poorly IL-31 by still of IL-31 are expression expression preferential IL-31 a modulating (T factors to the point and ies IL-31 of source The dis- system neuroimmune immune future. and the the inflammatory and in of IL-31 airways treatment and the gut for skin, of importance eases translational its IL-31/IL31RA/OSMR and the communication of neurons. role target iological activate to IL-31 of airways. and others, IL31RA/OSMR tivates H 2). + 6,28–31 T 1,5,9,10 3,5–7 H el sudrpiaycnrlo L4weesI-3siuainsest os L3 secretion IL-31 boost to seems stimulation IL-33 whereas IL-4 of control primary under is cells 2 H H el i TT-eedn euaino 1S2receptor. T1/ST2 of regulation STAT6-dependent a via cells 2 el,snoynre n eaioye,teeyiiitn namto,eihla dysregulation epithelial inflammation, initiating thereby keratinocytes, and nerves sensory cells, 2 ikn mueclst pteimadtenuoa ewr ntesi,adpoal logut also probably and skin, the in network neuronal the and epithelium to cells immune linking 6 oehr hs tde on ta seta oeo L3 o h erimn communication neuroimmune the for IL-31 of role essential an at point studies these Together, eetlresaetsu aksreigapoc ofimdams xlsv xrsinof expression exclusive almost confirmed approach screening bank tissue large-scale recent A 32,33 + nrdra plcto fI-1ide ed osnain fic,udryn h capacity the underlying itch, of sensations to leads indeed IL-31 of application Intradermal CD4 β ngntclymdfidmc,oeepeso fol igectkn (demonstrated cytokine single a only of overexpression mice, modified genetically In inldmesI-1epeso one-euaigteI- ffc.T effect. IL-4 the counter-regulating expression IL-31 dampens signal + β muecells. immune eetrepesn oslro agi DG ern n eaioye,among keratinocytes, and neurons (DRG) ganglia root dorsal expressing receptor 9 h rncito fthe of transcription The H β el.Ntby u nweg bu h omncto ewe IL-31 between communication the about knowledge our Notably, cells. 2 H ste ieetaefo aıeTclsdpneto L4sgaigfrom signaling IL-4 on dependent cells na¨ıve T from differentiate they as 8 el xrs nymdrt L3 eessnedffrnito fT of differentiation since levels IL-31 moderate only express cells 9 ee esmaieorcretudrtnigaottepathophys- the about understanding current our summarize we Here, 11 Stott β xsi knadmcs,wt nepai nneuro-immune on emphasis an with mucosa, and skin in axis tal et H el npriua)adi IL-31 if and particular) in cells 2 β. Il31 rps hti uasI-1epeso nCD3 in expression IL-31 humans in that propose . 4 hl h L4sga ntae L3 xrsin the expression, IL-31 initiates signal IL-4 the While 23,24 eei T in gene 13,14 o xml,I-1idcdbtp natriuretic b-type induced IL-31 example, For oee,i ean nla o secretion how unclear remains it However, 20,21 18,19 H n poal L4pouig mast producing) IL-4 (probably and 2 hog nao-ee mechanism, axon-reflex an Through fe ciaino yoiereceptors cytokine of activation After 15,25–27 23,24 9,11,12 utpepuioes hi co- their pruritogens, Multiple + CD4 h asii eetrTRP receptor capsaicin The ncnrs,TGF- contrast, In + + T H ye2Thle cells T-helper 2 type el ol aka mark could cells 2 25 32,34 H nhmn,our humans, In el,i com- in cells, 2 oee,a However, β a a has 15–17 H 22 + 9 Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ains eu L3 n L3 eesaefudt eicesdwe oprdt elh volunteers, healthy to compared intradermally. T when applied from increased when IL-31 be of response secretion humans, to itch the In found stimulate late might are elucidated. rather IL-33 levels be that a IL-33 hypothesis to evokes the and remain but although nurturing signaling IL-31 accepted, pruritogen firmly IL-31 serum is a of AD patients, as as role such pathophysiological acts disorders pruritic the IL-31 and about pruritus in aspects axis precise IL-31/IL31RA the of role skin The the in axis IL-31 The immune incoming the the senses with of sites which cytokine IL31RA/OSMR epithelial a T barrier, IL-33, connecting and T epithelial including receptor cells of “alarmins” mast T1/ST2 an of eosinophils, cognate activating by release its by by through protected system these signals are to which respond sites family can IL-1 Mucosal and allergens, cell or epithelial sites. pathogens of mucosal regulation at the OSM. processes in and well-described, family IL-31 (GIT). is IL-6 by tract receptor the activated gastrointestinal of and be members skin can for lung, role in a function established have diseases studies mucosal Multiple changes in and role inflammation, AD. its itch, for and of characteristic IL-31 severity density the fiber nerve into and epidermal feed recruitment the then cascade’. of neural could inflammatory IL-31 requires the communication of of immuno-neuronal model permeability. maintenance recruitment and eczema and vascular subsequent initiation chronic established, and the a imprinting for vascularization neuronal in process mouse infiltration, the stimulation a in ‘allergic cell in early activation that immune conducted suggests study preceed author recent occur might a The changes changes However, neural that AD. neural continuous assumption in that the utilizing signals with AD inflammatory line of in on-going is model to This patients. response stimuli. direct STAT3-dependent AD minimal induction in to a in the patients with density by AD in along achieved fibre sensitivity’ neurons activation. is nerve sensory pathway density sensory small-diameter PI3K/AKT fibre epidermal via of nerve survival quantity neuronal and cutaneous of extension in control branching, increase vehicle-treated in IL-31 than IL-31-mediated network increase metabolism. that neural The cutaneous and revealed denser survival a neurons mice. develop proliferation, weeks DRG over neuronal stimulus IL-31-activated chemical IL-31 in continuous in or involved analysis mice) further transcriptomics-based KO is TRPA1 conducting (TRPV1, study genetically itch. A IL-31-mediated since abrogate IL31RA can to TRPV1 linked of functionally blocking are ( channels neurons ion DRG ( neurons. human neurons sensory DRG size IL31RA-expressing large-diameter small-to-medium and by cells expressed T minantly IL-31-expressing between link skin-infiltrating T nerves), that (sensory ring ganglia root CD11b dorsal future. and human -13 the cells in IL-4, mononuclear in found for verified/falsified be levels can be expression expression both, to their IL31RA Furthermore, to for needs respect course, levels with of low differ While showed This, patients all. -31. others which not and in mRNA, but disease IL31RA. IL31RA patients, heterogenic or and of molecular IL-31 amount mRNA and either significant IL-31 for a levels for in low levels found some high were showed IL31RA pruritus. patients and alleviated IL-31 some and of lesions levels skin expression of ted healing induced mice IL-31-overexpressing itch.of and eczema with phenotype H ypoye eut neetv erto fI-1fo el,wihcnsbeunl activate subsequently can which cells, T from IL-31 of secretion effective in results lymphocytes 2 H el ersn h ansuc fI-1 h L3 xscudsrea togneuro-immune strong a as serve could axis IL-31 the IL-31, of source main the represent cells 2 β + pteilcls ern n isersdn muecells. immune tissue-residing and neurons cells, epithelial 46,47 + < vdnei mrigfrasgicn oeo L3 eitn inflammatory mediating IL-31 of role significant a for emerging is evidence el,etbihn nipratrl fI-1i ua Da el Conside- well. as AD human in IL-31 of role important an establishing cells, 1 50 nvivo in nadto,ipatto fGBegcitrern notesia cord spinal the into interneurons GABAergic of implantation addition, In μ )aemil IL31RA-negative. mainly are m) 5 hl h ontemeeto S neato ihiscognate its with interaction OSM of effect downstream the While mgn fprpea esr evsadbodvsesimplicates vessels blood and nerves sensory peripheral of imaging 6 hsrsl uprstehptei bu Dbigaclinically a being AD about hypothesis the supports result This H lymphocytes. 2 5 6 38–42 43–45 37 hs nig a atyepanteincreased the explain partly may findings These hc rbbyacut o h ihr‘skin higher the for accounts probably which uoa pteilclsepesOSMR express cells epithelial Mucosal + 48,49 el onuoa IL31RA neuronal to cells T < 36 npriua L3-rvnactivation IL-33-driven particular In 30 37 nmc,bt RV n TRPA1 and TRPV1 both mice, In upeupe ierciiga receiving mice Pump-equipped μ )c-xrsigTP1while TRPV1 co-expressing m) 5,36 H 35 el reihla cells epithelial or cells 2 h eetri predo- is receptor The nA ains eleva- patients, AD In 40 + ihearly With structures 50 nAD In β that 40 Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. asv nu fimn el nldn T inflammation. IL31RA, including tissue cells amplified express immune to of leading CCL22, influx and massive (TNF CCL5 alpha CCL2, factor necrosis as tumor such as cells. such T cytokines - pro-inflammatory regulatory and of or increase. number antigen effector IL31RA subsequent either the and CD1c activate activation capture STAT-1 human - in CD4 primary which TLR of respective as (DCs), exposure the and such cells keratinocytes, of Like activation allergens dendritic system, subsequent resident or immune the tissue on pathogens adaptive depending are invading immune the adaptive (APCs) (PRRs) of the cells receptors cells of antigen-presenting pattern-recognition to phagocytes colonization or Patrolling them skin TLRs present system. to via immune and IL-31 adaptive recognize IL31RA- linking and system keratinocytes, increased innate human cytokines the in between ‘atopic’ interplay nonspecifically, release or immunity. act CCL2 components to innate as wall subsets, and IL-31 well cell cell as an T bacterial levels multiple expand by OSM-expression activate to (TLR)-2 to ineffective known receptor is be toll-like SEB might However, thereby yet. T and tested pre-existing been to not subject has are T cells T in T decreased IL-31 involved with allergen-specific be HDM-reactive associated that patients of indicates AD frequencies finding chronic elevated This of Recently, skin-colonizing periphery the from antigens patients. in observed originating (HDM)-derived AD in mites antigens bacterial observation dust by AD-associated common house cells with T or T cutaneous subset (SEB) the memory of cell B phenotype enterotoxins effector T the staphylococcal this enhances as of such Challenge superantigens (HLA-DR). antigen-DR (CD3 cells histocompatibility T pro-inflammatory memory in skin-resident onset. of IL-31 AD importance functional the emphasize of observations IL31RA Recent importance epidermal the modulate(s) highlighting that candidates, and sys- factor(s) are environments. pruritus immune critical BNP inflammation, and The of like skin AD. progression ropeptides AD the of the in in progression between levels result thus expression loop would barrier, feedback circuit skin That positive impaired a 1). (Figure completing communication thereby tem IL31RA IL-31, of via levels elevated keratinocytes expresses IL-31. skin for CLA AD-derived target of of ‘sensitized’ epidermis a the forms However, and anticipated. but known not patients. CLA since chemokines cell-attracting CCL25. (CLA immune and various antigen CCL22 of release CCL17, keratinocytes. the CCL4, from initiates as IL-31 peptides such therapeutic development. antibacterial desirable AD of during a release process tant the be for not needed might vitro are IL-31 In signaling IL-31 of IL-31 of effector doses downstream of low a inhibition since as complete network outcome, However, cytokine IL-1 differentiation. the skin identified and and barrier and expression skin signaling. function filaggrin in barrier in involved envelope. deficit genes skin lipid the of by impaired the depicted of as defects reduction differentiation well ( a induced as plakoglobin signaling junction thickening IL-31 reduced models, epidermal to skin with due integrity IL-31 mechanical associated impaired study recent A in vivo. + 51 aafo os eaioye ugs novmn fI-1i muecl erimn,a impor- an recruitment, immune-cell in IL-31 of involvement suggest keratinocytes mouse from data 55 rbbyIL-31 probably , 54 10,57–59 + ntesi,I-1efre iseatrtosta r yial eni Dptet Fgr 2). (Figure patients AD in seen typically are that alterations tissue enforces IL-31 skin, the In hte L4 n L1-rdcn CLA IL-13-producing and IL-4- Whether codnl,aair-eitdI1 lcaewseetv oargt L3-eitdls of loss IL-31-mediated abrogate to effective was blockage IL1R anakinra-mediated Accordingly, el r bnatalre-ecieTclsi h iclto n einlsi fAD-affected of skin lesional and circulation the in cells T allergen-reactive abundant are cells T 23,24,56 + -xrsigTclst h pdri.Ti muecl usti fmjritrs nAD in interest major of is subset cell immune This epidermis. the to cells T )-expressing H 64 oto h knrsdn eoyTclsaeatgneprecdadepesstesurface the expresses and antigen-experienced are cells T memory skin-resident the of Most 1T3 programming. 31-Tc31 n htI-1fntosa uvvlsga oeigtert faotssi these in apoptosis of rate the lowering signal survival a as functions IL-31 that and 56 nvivo in rmn fTcls oee,i ope rcs,wihrle na intricate an on relies which process, complex a is however, cells, T of Priming + -T H el otesi i ees fceoie,wihi unfrhractivate further turn in which chemokines, of release via skin the to cells 2 sntkonyt oee,poiflmaoysgassc sIFN as such signals pro-inflammatory However, yet. known not is 53 eeepeso nlsscnre ietI-1dpnetregulation dependent IL-31 direct a confirmed analysis expression Gene 10 62 A-odtoe’krtnctscudpreut h recruitment the perpetuate could keratinocytes ‘AD-conditioned’ H 1 h aaiyo AseicTclst rdc n ert IL-31 secrete and produce to cells T SA-specific of capacity The el n oiohl.Arcn td eot hteosinophils that reports study recent A eosinophils. and cells 2 C1 n C2,frisac,rcutctnoslymphocyte cutaneous recruit instance, for CCL22, and CCL17 H pool. 2 + 6 + 63 + n ooyedrvddnrtcclst L3 results IL-31 to cells dendritic monocyte-derived and CD3 L3-tmltddnrtcclssceea extensive an secrete cells dendritic IL-31-stimulated elsubset. cell T 60,61 + el rseicsbye xrs L3 is IL-31 express subtypes specific or cells T tpyooclaureus Staphylococcal uhpiigadepnino skin-resident of expansion and priming Such Jup + 56,60 eprcls h oteffective most The cells. helper T eeexpression. gene ) 63 oegnrlsiuainof stimulation general more A H Cdrvdctknsidc a induce cytokines DC-derived 1/T α ,I-,I- n chemokines and IL-8 IL-6, ), H -c n htI-1may IL-31 that and 2-Tc2 H n c/c ratios. Tc1/Tc2 and 2 + CD45RO S)adHMi a is HDM and (SA) 52 + norganotypic In el were cells T + CLA γ rneu- or + for ) 54 62 Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. utpso Dwihwl rfi h otfo h urn n uueteaistreigI-,-3ad-31. and -13 IL-4, targeting the therapies concerns understand future better safety and to current long-term important the No be from most will the it nemolizumab. profit disease 0.5-mg/kg will heterogeneous which with clinically dermatitis. AD a 64 Finally, of atopic is week subtypes event. moderate-to-severe AD adverse at Since in frequent observed identified. published most were was was the itch was study reaction extension of site provement long-term Injection phase-II, group. recent placebo a the versus to weeks) compared 4 group every 24, adult mg, week (60 Japanese not investigated nemolizumab P but weeks. study with 8, 16 treated extension week over pruritus follow-up at and placebo phase-III already AD A group moderate-to-severe profile. placebo with safety patients (IGA), vs. acceptable Assessment AD (ppNRS) overall Global Scale moderate-to-severe an Investigator’s Rating uncontrolled with EASI, Numerical with improving Pruritus adults markedly Peak efficacious, in and most weeks the 24 was over nemolizumab pruritus. weeks severe group 4 placebo with every and associated administered treatment mg) con- in In different 90 nemolizumab dosages. significantly Thus, tolerated. and chosen not well with group. were and weeks placebo BSA) safe 12 the was (EASI, at in AD, endpoints reduced 15.7% moderate-to-severe secondary was in (BSA) vs. the pruritus area groups trast, improved surface nemolizumab significantly body the weeks affected in 4 The 19.4% every placebo and with group. 20.0%, placebo reduction 7.5%, the itch by in 20.9% -26.6% to versus topi- groups compared of respectively, nemolizumab use 63.1%, decreased 59.8%, 43.7%, and (P by efficiency itch therapy. sleep reduced improved corticosteroid mg/kg) with 4, anti-IL31RA combination week humanized in at a event 50% of about efficacy hydrocortisone. to the cal pruritus 1). after assessing reduced pruritus (Table trial safely, of dose I/Ib reduction and dose-dependent subcutaneous phase marked clinical single a revealed a a nemolizumab) of (CIM331, data antibody first monoclonal the humans, In cynomolgus and human of administration reduction.27714851 by levels. caused serum was IL-31 phenotype IL-31. AD-like decreased an with where AD. associated mon- monkeys, with and anti-canine cynomolgus dogs month caninized in a a symptoms over lokivetmab, itch for of alleviates administration antibody, subcutaneous anti-IL-31 that oclonal demonstrated AD al., and cytokine. et models the Michels mouse of AD homology in inter-species itch low prevented the effectively despite NC/Nga- antibody in neutralizing a approaches scratching. by patients. reduced inhibition IL31RA of IL-31/IL31RA of observation Early first blocking the that axis. in IL-31/IL31RA resulted the mice inbred also T (FDA). block as in Administration efficiently designated IL-31 Drug of been that and role has Food multifaceted and US the pruritus the Considering and by lesions AD skin for of therapy improvement breakthrough robust a and rapid a achieved treatment. treatment IgG4 AD human for (IL4R both, fully receptor or a IL13, dupilumab, or IL-4 of targeting antibodies of development trials T clinical The and IL-31 of importance Translational additional of recruitment the T to leads including cells T CD68 effector and of eosinophils expansion clonal Uncontrolled cascade. inflammatory cells. < < .0) enES cr,DraooyLf ult ne DQ)soeas mrvdi nemolizumab in improved also score (DLQI) Index Quality Life Dermatology score, EASI Mean 0.001). .1.Cagsi h ceaAe eeiyIdx(AI cr ee-30,-23,ad-09 nthe in -40.9% and -42.3%, -23.0%, were score (EASI) Index Severity Area Eczema the in Changes 0.01). 65 75,79 H hs L3 inln a ffrasria datg oA-soitdesnpisrifrigthe reinforcing eosinophils AD-associated to advantage survival a offer may signaling IL-31 Thus, yoie L4adI-3hv eetybe dnie scnrlmdaoso D edn othe to leading AD, of mediators central as identified been recently have IL-13 and IL-4 cytokines 2 69–74 oevr lcaeo L3 inln sn nat-L1Aatbd eutdi infiatitch significant in resulted antibody anti-IL31RA an using signaling IL-31 of blockage Moreover, H el,b rsnigSB rHMatgnt isersdn rifitae na¨ıve T-cells. infiltrated or tissue-resident to HDM-antigen or SEB- presenting by cells, 2 L3-eedn rrtcatvt a endsrbdi ie aie,piae n humans and primates canines, mice, in described been has activity pruritic IL-31-dependent α ,vldtda seta oeo h T the of role essential an validated ), 72 + olwu ra ocue h aeueo eoiua ihn infiatadverse significant no with nemolizumab of use safe the concluded trial follow-up A 74 macrophages. ee eoiua eue h einVSsoeb 28 s lcb (21.4%, placebo vs. 42.8% by score VAS median the reduced nemolizumab Here, 80 80 ocmtn oia otcseodtetetwsalwd ee 0mg 30 Here, allowed. was treatment corticosteroid topical Concomitant hs-I lncltilivsiae h ffcso eoiua 1,30, (10, nemolizumab of effects the investigated trial clinical phase-IIb A κ 10 oolnlatbd idn othe to binding antibody monoclonal 72 ial,atvtdDspriiaei h ciaino CD4 of activation the in participate DCs activated Finally, eoiua niie L3-eitdcl inln efficaciously signaling cell IL-31-mediated inhibited Nemolizumab H -rvnA,eot aebe nesfidt eeo agents develop to intensified been have efforts AD, 2-driven 73 nti hs-Iciia ra,nmlzmb(.,05 2 0.5, (0.1, nemolizumab trial, clinical phase-II this In 7 75–77 H tp-)iflmaoyai nA.Dupilumab AD. in axis inflammatory (type-2) 2 68 78 eea olwu tde demonstrated studies up follow Several iia eut aebe bandin obtained been have results Similar 77,78 α- h eraeo thwsstable was itch of decrease The 34,66 uui fteinterleukin-4 the of subunit 67 npriua,tesuccess the particular, In + cells, T 71 Im- Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. nhmnbocileihla el n oclue ihesnpis L3 ln ri oprto with cooperation in or alone IL-31 eosinophils, with co-cultures and asthma. cells triggered that epithelial T levels bronchial activity increased human and In health improved to due probably asthma, and stems pathogens nemolizumab. rather invading lung with but against by cells signal continuously secreted alarm T situation. is an allergic by IL-33 as Interestingly, expressed the reactions exclusively IL-4. inflammatory to to allergens be asthmatic leading respond not during that phenotype would cells lung asthmatic IL-31 epithelial the the in culprit asthma. cells of allergic the unidentified of progression that from marker the a suggests as support study serve might to this IL-31 found that some was by IL-31 notion since essential, signaling be downstream by ligand T its In the of example, engagement For after donors. downregulated between abundance transiently IL- effects. receptor is of in role IL31RA differences profound of and a expression IL31RA indicates of This expression proliferation. inducible such suppressing the proteins homeostasis. and cycle changes cell tissue (CDC2), of morphological in CDK1 expression and 31 and induces interactions. CDK6 regulation cell-cell B1, IL-31 impaired in cyclin an (A549), reduction and as arrest a line cell-cycle and induces cell extensions activation IL-31 podosomal adenocarcinoma of lung formation determined. by human be characterized epithelial-like to yet the has activation In processes, STAT3 regenerative via in epithelium apoptosis. involved intestinal of is within inhibition and roles and responses STAT1. proliferation as anti-inflammatory such as and targets such IL-6 proinflammatory phospho- “classical” STAT3 both other increases to the unaffected. of linked levels IL-31 any pERK whereas of leaving STAT5, expression the and and initiate responses ERK STAT5 STAT3, attenuating of while intestine rylation, phosphorylation and cascades. balanced signaling sinus downstream to nasal distinct leads activate lung, can human agonist the IL31RA/OSMR each pathways, to of affinities sites equal mucosal with engage in detected 3). been (Figure has signaling IL-31 Intestine Recently, and Airway Mucosal in IL-31 eodr hleg fioae yp oeclswith cells node lymph absent. was isolated IL31RA of when challenge tissue secondary IL31RA lung parenchymal model, effects the this ameliorating of In described inflammation inflammation. intensified al. 2 displayed et type but in Perrigoue pulmonary signaling, cytokine of function. inflammatory model airway murine an in a than soni IL-31 in rather axis for IL-31/IL31RA regulatory role the a dual of as a autocrine suggesting IL-31 the lung, and describe cells, the however, inflammatory studies, of Subsequent recruitment the tion. in fac- cells, involved growth epithelial are endothelial of EGF (VEGF), remodelling and factor VEGF growth CCL2, endothelial (EGF)). (vascular tor factors growth and (CCL2) chemokines eutn narfie oto fctkn rdcin oee,teeeet eeasn nflydifferentiated fully in cells, absent T were undifferentiated effects these in However, GATA-3 production. with cytokine T axis of effector IL-31/IL31RA control refined the a of in engagement resulting re- regulatory tissue a pulmonary indicate in dings IL31RA T resulting elevated in (AAMs) and production macrophages Na¨ıvecapacity CD4 cytokine activated fibrosis. in alternatively and increase of modeling the signaling frequency However, IL31RA elevated of an tissue. function to anti-inflammatory lung stronger parasite-affected a the suggest findings in these models, inflammation lung H yoie I- rI-3 a hw oatrtepouto fiflmaoyctkns(L6 IL-8), (IL-6, cytokines inflammatory of production the alter to shown was IL-13) or (IL-4 cytokines 2 H gs ogn ntesalbodvseso h ug eeo umnr rnlms u oIL-4/IL-13 to due granulomas, pulmonary develop lung, the of vessels blood small the in lodging eggs, -oiae shai rnnatmtcara namto hne nI3R bnac could abundance IL31RA in changes inflammation airway non-asthmatic or asthmatic 2-dominated 81 88 H 81–83 el.Tu,I-1atvto fatgnpeetn el eg arpae)apast restrict to appears macrophages) (e.g. cells antigen-presenting of activation IL-31 Thus, cells. 2 u per ofi osga nploayT pulmonary in signal to fail to appears but ugeihla el xrs L1A OSMR IL31RA, express cells epithelial Lung 11 80 neetnl,atm a on soeo h oedpnetsd ffcsi lncltrials clinical in effects side dose-dependent the of one as found was asthma Interestingly, h shai vnshv xlsvl enosre nptet ihapre-existing a with patients in observed been exclusively have events asthmatic The -/- H 81 iesoe nicesdpouto ftp- yoie I-,I-,I-3 upon IL-13) IL-5, (IL-4, cytokines type-2 of production increased an showed mice -yoiepouto ihu ieetainit T into differentiation without production 2-cytokine fnt,tersosso ugeihla el oI-1atvto a aydeto due vary can activation IL-31 to cells epithelial lung of responses the note, Of 89 niaiga vrl r-namtr oefrI-1i umnr inflamma- pulmonary in IL-31 for role pro-inflammatory overall an indicating + el rmIL31RA from cells T β fln pteimadatvt omnsga transduction signal common activate and epithelium lung of 84,85 8 .mnoiegantigen egg mansoni S. st hte L3 sipiae nteefunctional these in implicated is IL-31 whether to As -/- H el ou-euaeI-1rlaelvl nan in levels release IL-31 up-regulate to cells 2 iedmntae nagetdproliferative augmented an demonstrated mice β n p3.Atog oh S n IL-31, and OSM both, Although gp130. and 51,86,87 81 otayt nig nteskin, the in findings to Contrary otayt nta tde in studies initial to Contrary . o ntne S activation OSM instance, For H 90 81 oaie el.Teefin- These cells. polarized 2 ieifce with infected Mice 81 TT inln a been has signaling STAT3 ete S o IL-31 nor OSM Neither 81 -/- Furthermore, ieleads mice .man- S. 90 Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. fI-1ai niiino Dost rgeso n eouin swl sisipc eiepuiu on pruritus beside impact its as well as resolution, and AD progression of benefit understand onset, population to help AD heterogenous will an the on studies achieve long-term stratify inhibition IL-4R large-scale, to to More IL-31-axis the sufficient how benefit. of of be evaluation ‘personalized’ may success best further pathway the the demands IL-31 for However, patients patients the patients. AD of some blockage in antibody. improvement pathophysiology sole in dupilumab anti-IL31RA with that AD outcome along using suggests in therapeutic itch patients is AD IL31RA in acceptable AD severe it of reduction in to pruritus, marked importance studies, moderate a and The in some validating AD cytokine. trials in ‘itchy’ with recent eczema, an associated and of than early been more by predominantly demonstrated is has was IL-31 IL-31 that of clear function now IL-31. biological of the role intestine. Although pro-inflammatory perspectives inflamed rather future a the reveal and in confirmation skin remarks await IL-31 cytokines the results Concluding in the of type-2 intestine, observations function of and since lung immuno-regulatory studies production in additional an enhanced consistent by are implying an observations IL31RA, demonstrated these T although group of a Nevertheless, the absence towards tissue, the cells lung in na¨ıve T inflamed skew in to 31/IL31RA present was IL-4 myofibrob- subepithelial colonic human in to revealed led been activation further dependent α has IL-31 IL-31 of lasts. effect pro-inflammatory inflammation. intestinal A OSMR in (TNF axis and cytokines IL-31 IL31RA, pro-inflammatory however, the IL-31, cells, with of induced HCT116 involvement correlated (LPS) colorectal which lipopolysaccharide In patients bacterial missing. UC still and and of are CD UC levels of or elevated lesions CD revealed colonic analysis inflamed and expression. Expression is in IL-8 inflammation cells. mRNA (CD). IBD lesional T mucosal OSMR disease (IBD). and regulatory Crohn’s with disease IL31RA and and presenting IL-31, bowel (UC) effector tract inflammatory colitis in ulcerative gastrointestinal imbalance with described, an the associated to of be due disorder to ulceration autoimmune seems imbalance frequent IL-31 a intestine, the In patients of inflammation. turbinate allergic inferior nasal the during in the upregulated of found expression further induced rhinitis. were IL31RA T allergic and IL-31-amplified NPs with IL-31 the in of elevated to levels is due T mucosa. Expression IL-31 probably especially sinus of outcome, lymphocytes, expression the clinical The of with of inflammation. profile. infiltration correlated (NP) inflammation type-2 levels an a polyps protein by as nasal IL-31 characterized now and histologically of considered AD pathogenesis eosinophils, to and the cells, similar in are implicated polyps been sal recently has IL-31 inflammation. airway during system immune adaptive cells. lung T na¨ıve and of proliferation the al neto tg n oacneso fteimn epnet T a to response immune the of conversion a infection. to parasitic IFN and of stage model infection murine early a in muris hu- responses Trichuris in signaling immunological in IL-31 with inflammation of associated intestinal DCs. types, role cell and chronic the nerves promoting to in disease- cells, Similar IL-31/IL31RA in T traits effector/regulatory of signaling cells, function IL-31-induced epithelial the of intestinal assessments including elucidate detailed To necessitate will far. mans so shown been metalloproteinases. (GRO- γ. 83 ergu ta.dmntae htI-1epeso nrae ne namtr odtoswhen conditions inflammatory under increased expression IL-31 that demonstrated al. et Perrigoue α 90 ,CC1 ooyeceotrcatpoen3(C-) XL GO3,I- n various and IL-6 (GRO-3), CXCL3 (MCP-3), protein-3 chemoattractant monocyte CXCL1, ), hrfr,I-1mysprs oeint muecls hrb euaigatvto fthe of activation regulating thereby cells, immune innate some suppress may IL-31 Therefore, ntae rmn fT of priming initiates 95 82 91 h namtr mato IL-31 of impact inflammatory The 94 L1Apiaiylclzdt umcslgad n tmlto fA4 cells A549 of stimulation and glands submucosal to localized primarily IL31RA ui 5AC mucin eodti ecitv nig nI-1seicipc nclua ehnssin mechanisms cellular on impact IL-31-specific an finding, descriptive this Beyond H ieetae el ihu marn hi nie-rsnigcpct in capacity antigen-presenting their impairing without cells differentiated 2 91 ( MUC5AC H .mansoni S. el n usqetpouto fT of production subsequent and cells 2 nvitro in eesgetn oefrI-1i uu overproduction mucus in IL-31 for role a suggesting gene ) rdcino L8(XL) rwhrltdoncogene- growth-related (CXCL8), IL-8 of production idcdara namto,I-1/3R a been has IL-31-/L31RA inflammation, airway -induced 9 H hntp.Lk hi eut nterl fIL- of role the on results their Like phenotype. 2 94 nvivo in 92,93 nteitsia pteillyrhsnot has layer epithelial intestinal the on w ao ye fIDhv been have IBD of types major Two H 72,74,80 -oiae hntp including phenotype 1-dominated β RAepeso,suggesting expression, mRNA H h ucs fteetrials these of success The ffco yoie nthe in cytokines effector 2 83 neto fmc with mice of Infection α- niiigantibody inhibiting H 2-skewed α, 82 IL-1 Na- H β 83 2 ) Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. .Rotra ,Geg ,ShedrS,BnetN,Seno .Nuoa oto of control Neuronal M. Steinhoff NW, Bunnett organ. SW, neuroimmunoendocrine Schneider a as T, skin Goerge Diseases. the Skin D, Autoimmune doi:10.1152/physrev.00026.2005 in function: Roosterman IL-31 Cytokine skin Pruritic the of 8. Role U. helper Raap T N, Immunol mediates Patsinakidis Front receptor BF, skin IL-31 Gibbs atopic neuron-expressed 7. in sensory pruritus A TRPA1. and and al. cells TRPV1 et T of doi:10.1016/j.jaci.2013.10.048 T, between Involvement Akiyama link X, itch: new Wang cell-dependent a F, IL-31: Cevikbas al. sig- 6. et the AI, of Lauerma Characterization A, HM. Muller inflammation. GP130- Hermanns E, Sonkoly receptor. PC, of Heinrich cytokine 5. isoform BE, gp130-like long Lippok novel the S, the of Pflanz doi:10.1074/jbc.M401122200 of S, expression capacities Radtke signaling. Predominant naling A, interleukin-31 Dreuw al. for 4. et required J, Froger is A-HL, receptor http://www.ncbi.nlm.nih.gov/pubmed/15627637. Lak-Hal the (GPL) of cells, C, properties like T Diveu anti-inflammatory activated and by pro- The 3. produced S. cytokine Rose-John a D, Schmidt-Arras 31, interleukin-6. A, Interleukin cytokine Chalaris J, al. Scheller et 2. A, Hammond mice. C, in dermatitis Sprecher induces SR, Dillon 1. Leo, Novartis, Sanofi, Pfizer, MenloTx, Eli-Lilly, by Leo, Janssen, References Grants Galderma, Pfizer, Celgene, for UCB, consultant Regeneron. Novartis, a Eli-Lilly, Sanofi, is Janssen, MS Regeneron. Pfizer, MenloTx. interest. for of Leo, Speaker conflict Galderma, Galderma. any declare Celgene, not UCB, do Novartis, JB and FA MA, or needs AD, pathway polyposis), IL-31 statement (nasal the dual interest neutralizing a disorders of of has Conflict atopic itself role disease. IL-31 each as beneficial because for the well above, explored stage, mentioned as be disease as new to However, on diseases, to depending tract. skin lead gastrointestinal effect probably or of inflammatory will lung treatment models, the disease in the disorders and for organ- of options in array mechanisms the similar therapeutic an IL-31-induced understand a conditions, precise fully in the inflammatory to tissues However, Deciphering and homeostasis both nerves. probably during in lung as and skin acts cross-communicating or subsets and and likely tract vivo DC lung cells IL-31 GI cells, gut, resident the T of in understood. receptive of IL-31-axis responses to being disorders inflammatory signal inflammatory from nurturing regulatory skin, in far a in IL-31 and observed of tract. preliminary as involvement pulmonary GI stage and fashion the The intestinal this and on effect lung clear. at its skin, less is IL-31, namely of is sites, function mucosal cutaneous populations the all cell understand enhance of to and cells begin develop we epithelial diseases. further while in However, pruritic to responses therapy-refractory order regulatory currently in triggers of understand Il-31 treatment to the important for be ‘toolbox’ will types. itch therapeutic considering cell target, of our various treatment types in valid different a signaling in as IL-31 diseases. inhibition recognized of be pruritic might capacity certain axis growth-promoting of IL-31 the the therapeutics patients itch as nodularis cancer-associated biologicals prurigo in in anti-IL31/IL31RA example, nemolizumab of of applicability trial recent the A suggests dysregulation. barrier and (eczema) inflammation and nvivo in leg lnImmunol Clin Allergy J 091:33 doi:10.3389/fimmu.2019.01383 2019;10:1383. . tde ilne ob performed. be to need will studies ici ipy Acta Biophys Biochim a Immunol Nat 06172:1-1.doi:10.1016/j.jaci.2005.10.033 2006;117(2):411-417. . 0457:5-6.doi:10.1038/ni1084 2004;5(7):752-760. . 0111()8888 doi:10.1016/j.bbamcr.2011.01.034 2011;1813(5):878-888. . 10 leg lnImmunol Clin Allergy J ilChem Biol J u yoieNetw Cytokine Eur hso Rev Physiol 37,52,97 h ffiayo h IL-31-axis the of efficacy The 2004;279(34):36112-36120. . 2006;86(4):1309-1379. . 2014;133(2):448-460. . 15(4):291-302. . nvitro in 96 , For ex Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 6 onM.Mlclrdseto fitch. of dissection Molecular itch. of circuits MA. and cells Dermatitis- molecules, Atopic Hoon the doi:10.1016/j.conb.2015.01.017 itch: in an scratch SNAREs 26. we of Why MA. Role Hoon Neurosci M. SR, Nat Wilson Steinhoff DM, Bautista T, 25. Buhl J, Communication. dermatitis. Buddenkotte Skin-Nerve atopic and doi:10.1016/j.jid.2019.04.017 J, IL-31-induced Secretion Wang underlying Cytokine mechanism Related J, New Meng al. 24. et M, Feld Immunol M, Clin Moriyama Allergy J, Meng 23. itch. of elicitation cutaneous disease. St of 22. receptors: mechanisms their the and Tachykinins and NW. Bunnett control C, doi:10.1152/physrev.00031.2013 Pothoulakis physiological P, Geppetti to B, contributions Mentzer von MS, Steinhoff a 21. of management pruritus. and Chronic Evaluation practice. A. Clinical neu- doi:10.1056/NEJMcp1208814 JD. Ikoma Bernhard Neurophysiological, J, G, Yosipovitch Buddenkotte B´ır´o20. T. K, E, Chong I, pruritus. Wei Yeh chronic F, with M, patient Cevikbas M, Maurer pruritus. Steinhoff 19. M, of Schmelz basis J, neuroendocrine doi:10.1038/sj.jid.5700231 Bienenstock and M, roimmunological, Steinhoff pathophysio- and 18. management, presentation, itch. Clinical AL. neuropathic Oaklander of Szab´o Itch. IL, logy M, Schmelz of M, Pathophysiology Steinhoff 17. and Physiology more EA. for Lerner brain doi:10.1152/physrev.00017.2019 the F, Its scratching Cevikbas research: and pruritus 16. Signaling in 31 Frontiers M. Interleukin B´ır´o therapy. Steinhoff Functional M, itch T, Schmelz effective for R, Prerequisites Paus 15. al. (SOCS3). 3 et Signaling in S, Cytokine doi:10.1074/jbc.M115.661306 expression Ess of gene 24759. M, Suppressor IL-31 by Mittermeir regulate Regulation cooperatively E, Feedback JunB Maier and NFAT1 disease. 14. al. and gene et health IL31 E, in the Park cells of G-C, T activation Kim CD4+ Transcriptional H-P. JS, Kim Hwang in- M-J, 13. is Song J-J, IL-31 Lee Human STAT6. W-J, Yang and CB. NFAT J-H, by Schmidt-Weber Park K, S, Park Durham 12. D, inflammation. Pennino TH2-driven S, promotes Lehmann and doi:10.1016/j.jaci.2013.03.050 P, IL-4 Lavender by antigen- B, duced lymphocyte Stott cutaneous with dermatitis. associated 11. atopic is in with IL-31 IL-31 patients release al. in doi:10.1016/j.jaci.2005.10.046 cells et cells 425. Th9 M, T not Maurer homing but DYM, skin Th2 Leung positive Human J, J. Bilsborough Horejs-Hoeck 10. B, Bohle A, Duschl STAT6/NF- D, Werner a E, Maier 9. ne ,Seno ,ShezM esha ,MteD ue .Nuohsooyo pruritus: of Neurophysiology T. Luger D, Metze E, Weisshaar M, Schmelz M, Steinhoff S, ¨ ander κ 041()1512 doi:10.1038/nn.3619 2014;17(2):175-182. . -eedn way. 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J Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 4 igZ ali ,CxG ta.I- sa ninamtr yoierqie o otoln oa or local controlling for required cytokine antiinflammatory an is IL-6 al. et G, responses. Cox inflammatory colonic acute J, the systemic Gauldie in Z, receptor Xing interleukin-6 44. soluble and Interleukin-6 al. disease. et 1746.1999.01989.x bowel K, inflammatory Ina of K, mucosa Kusugami T, Hosokawa 43. dermatitis. atopic of 012-1246-0 lesions early therapeutic from dermatitis: sies atopic Hagstr to L, reference Emtestam special Der- 42. with Atopic fibers and nerve Itch and in Itch System implications. K. Immune Takamori the M, Tominaga Than 41. Important More System Nervous the matitis? Is diseases. EA. skin Lerner allergic 40. in interactions Neuroimmune Immunol M. 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Curr J Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 1 orsM,Gnae J oz L ta.CruaigCA ypoye rmcide ihatopic with variable children receptor from T-cell lymphocytes staphylococcal-related CLA+ bearing Circulating cells al. of et percentage JL, dermatitis. increased Corzo atopic an FJ, in contain Gonzalez dermatitis pathogens MJ, bacterial Torres of 61. Role B-L. Chiang C-T, Wang Immunol Y-T, acti- Lin modulates 60. dermatitis atopic with patients in activated pathology. doi:10.1016/j.jaci.2014.03.003 Cyclosporine epidermal are 1634. al. reverses cells et and M, pathways T by Rozenblit inflammatory counter-regulation vated memory A, IgG4 Shemer CLA+ S, pattern: Skin-homing, Khattri cytokine 59. K. IL-13-dominated Blaser an by cells. R, IgE T Disch memory regulate L, CLA- and Weigl the dermatitis CA, pati- receptor, atopic from Akdis homing in cells skin-selective M, T the Akdis allergen-reactive express 58. Circulating dermatitis primary al. contact human et allergic antigen. in MT, and lymphocyte-associated 31 Soler cutaneous dermatitis Perez interleukin atopic LJ, of with Picker effects ents LF, Functional Babi T. Santamaria Werfel 57. K, Baumert M, lymphocyte cutaneous Niebuhr keratinocytes. the S, with associated Kasraie are 56. transmigration dermatitis endothelial atopic and and specificity dermatitis Allergen contact K. ex- allergic antigen. Blaser in C, filaggrin cells Hauser T MT, of and Soler Perez LF, differentiation Santamaria 55. regulates IL-31 Network. Signaling al. IL-31-IL-1 et H K, 54. models. skin Czaja organotypic Y, doi:10.1016/j.jaci.2011.10.042 human Marquardt in C, pression Cell Cornelissen Epidermal Involves 53. Remodeling Skin IL-31-Driven Function. al. 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Data may be preliminary. 6 ozlsA,Hmhe R esmr E ta.Itrekn3:isrl ncnn rrtsand pruritus canine in role its Interleukin-31: al. et JE, Messamore WR, Humphrey AJ, antibody. monoclonal Gonzales humanized scrat- 76. a interleukin-31-induced by of A model monkey receptor Cynomolgus interleukin-31 al. human matol et of blockade T, Kuramochi depicts H, ching Kitamura of S, Trial Oyama Group. 75. Study Nemolizumab-JP01 Pruritus. with M, Dermatitis Kawashima Atopic doi:10.1056/NEJMoa1917006 H, for Agents Komazaki Topical T, and Dermatitis. Nemolizumab Matsumura Atopic for K, Antibody Kabashima A 74. Receptor Anti-Interleukin-31 placebo-co. al. Med et J double-blind, M, Engl Furue randomized, N JM, a Hanifin tolerabi- T, in Ruzicka safety, 73. evaluate dose to single dermatitis a atopic interleukin-31 antihuman with doi:10.1111/bjd.14207 of humanized 2016;174(2):296-304. patients a pharmacokinetics and CIM331, of volunteers and trial healthy first lity in The antibody, al. atopic et A H, moderate-to-severe Nakagawa receptor potential M, with Furue a O, patients Nemoto in 72. be Nemolizumab study. to al. extension shown et long-term doi:10.1016/j.jaci.2018.03.018 JM, is 1130.e7. II, Hanifin phase antibody M, Randomized, receptor Furue dermatitis: mice. K, Anti-IL-31 in Kabashima al. dermatitis 71. et and S, itch treating Ohyama doi:10.1111/bph.12823 for E, option Fujii therapeutic K, behaviour scratching Kasutani itch-associated severe upregula- 70. causes IL-31 and of ganglia administration root Repeated dorsal S. mice. in Saito in N, (IL-31RA) Akiyama A H, receptor Takeda IL-31 K, Miyagawa tes M, Tsuji I, Arai 69. dermatitis. atopic of be- model scratching 0625.2008.00766.x ameliorate a Anti-interleukin-31-antibodies mice: al. atopic NC/Nga et moderate-to-severe in C, Vestergaard haviour with Y, adults Sawanobori O, in Grimstad treatment 68. Dupilumab al. et JD, Hamilton dermatitis. 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Y, helminth with intestinal Du patients following in K, inflammation doi:10.4049/jimmunol.0802459 levels Guild 2009;182(10):6088-6094. cytokine and Th2 immunity C, of cytokine-dependent Zaph regulation Th2 in JG, IL-31 Perrigoue cells. of Role 83. epithelial J. Du lung Y, Zheng in polyps. J, nasal patterns Cheng H, response Ouyang 82. and reactions with oncostatin- and adults signaling Interleukin-31 doi:10.1074/jbc.M609655200 H. in 2007;282(5):3014-3026. Baumann distinct S, nemolizumab Rose-John mediate O, of Robledo P, M study Liang E, randomized Tracy S, 2B Chattopadhyay 81. Phase al. pruritus. et severe G, and doi:10.1016/j.jaci.2019.08.013 Pulka dermatitis antibody. rapid A, atopic neutralizing a Pinter moderate-to-severe monkeys IL-31 JI, cynomolgus an in Silverberg by induces 80. inhibited 31 be (IL) can Interleukin al. that et Venereol response MF, itch Maurer intense MS, and safety Holdren the KE, of Lewis with trial dogs 79. placebo-controlled client-owned in randomized, antibody blinded, monoclonal A IL-31 dermatitis. al. anti-canine atopic et caninized a KA, (ZTS-00103289), Kryda lokivetmab KF, of Walsh GM, dogs Michels owned 78. client in antibody monoclonal determination dermatitis. 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Immunology 2007;122(4):532-541. . 2020;145(1):173-182. . u cdDermatol Acad Eur J ilChem Biol J Immunol J . . Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ethnicity Participant Duration status Recruitment Phase Publication number Identifier design Study biologic of Mechanism PN and AD in efficacy nemolizumab by testing proliferation/survival trials cell completed progenitor for myeloid design of trial Regulation Clinical inflammatory 1: al. Table et of G, IL-31. Hangoc and production J, receptor IL-31 Li stimulates HE, Broxmeyer Interleukin-31 97. Med al. J Engl et N myofibroblasts. A, St subepithelial 96. Nishida colonic A, disease. human bowel activa- http://www.ncbi.nlm.nih.gov/pubmed/17487427. Andoh STAT1/3 inflammatory from and in Y, kinase upregulated mediators MAP Yagi is mediates expression 31 95. its Interleukin and al. cells et doi:10.1136/gut.2006.118679 epithelial J, 2007;56(9):1257-1265. intestinal Seiderer F, in Beigel tion J, Dambacher 94. doi:10.1517/14728220902762928 306. F C, Koenecke 93. ne ,YspvthG ea J ta.Tilo eoiua nMdrt-oSvr rrg Nodularis. Prurigo Moderate-to-Severe in Nemolizumab of Trial al. et FJ, Legat G, Yosipovitch S, ¨ ander 00328:0-1.doi:10.1056/NEJMoa1908316 2020;382(8):706-716. . rtrR C9adiflmaoybwldisease. bowel inflammatory and CCR9 R. ¨ orster aaeeN AN Japanese, 1/1b NA 2 wk; A:12 Part NA Completed wk 32 2B Completed NA wk 16 Completed 2 Japanese Completed wk 16 Completed 3 2020, al., et Kabashima 173740 JapicCTI- multi-center double-blind, controlled, placebo- Randomized, signaling downstream and activation receptor 31-dependent IL- blocking antibody monoclonal Anti-IL31RA IgG2 humanized CIM331; (CD14152; Nemolizumab κ x Hematol Exp ? 74 073( up )7-6 doi:10.1016/j.exphem.2007.01.028 1):78-86. Suppl 2007;35(4 . C0110 C0104 C0963 NA NCT01986933 NCT03100344 NCT03181503 multi-center double-blind, controlled, placebo- Randomized, signaling downstream and activation receptor 31-dependent IL- blocking antibody monoclonal Anti-IL31RA IgG2 humanized CIM331; (CD14152; Nemolizumab 2020, al., et Stander κ 96 ? 16 oernigXIAstudy XCIMA ranging dose multi-center double-blind, controlled, placebo- Randomized, signaling downstream and activation receptor 31-dependent IL- blocking antibody monoclonal Anti-IL31RA IgG2 humanized CIM331; (CD14152; Nemolizumab 2020, al, et Siverberg κ 80 xetOi hrTargets Ther Opin Expert ? n o Med Mol J Int group multi-center double-blind, controlled, placebo- Randomized, signaling downstream and activation receptor 31-dependent IL- blocking antibody monoclonal Anti-IL31RA IgG2 humanized CIM331; (CD14152; Nemolizumab atB 2wk 52 B: Part 2018, al., et Kabashima B: Part 2017, al et Ruzicka A: Part κ 2007;19(6):941-946. . ? 71 73 2009;13(3):297- . IgG2 humanized CIM331; (CD14152; Nemolizumab multi-center double-blind, controlled, placebo- Randomized, signaling downstream and activation receptor 31-dependent IL- blocking antibody monoclonal Anti-IL31RA white 2016, al et Nemoto 2 days 127 Gut κ 72 ? . Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ensoni h oslhr ftesia od niaigta L3 inln slkl novdi central in involved likely is signaling IL-31 that indicating neurons. cord, cord and spinal IL31RA/OSMR spinal hypersensitivity the of system, skin pruritic of sensitization nervous AD horn and causing central in dorsal pruritus the probably levels the In growth in IL31RA shown pruritus. neuronal high been peripheral enhanced demonstrate of endings to IL31RA/OSMR elevation nerve leads express an Sensory neurons stimulation sensory IL-31 TRPV1. mouse and co-express and also Human that pruritus. neurons and additional inflammation an skin trigger impaired CLA of that an a chemo-attractants IL-31-expressing and various and filaggrin of secrete (neuro)-inflammation as keratinocytes recruitment such Activated pruritus, genes AD differentiated envelope. peripheral terminally human lipid in of reduced In suppression results IL-31-mediated signaling epidermis. through function IL-31 the barrier IL31RA/OSMR Cutaneous of of keratinocytes IL-31. levels and elevated to shown) show (not keratinocytes eosinophils skin, and monocytes IL31RA/OSMR DCs, activate including can turn in which IL-31, downstream environment, pro- cell inflammation, and in involved type genes cell skin of survival. on expression cell the Dependent and controls liferation subsequently members. activation cascade factor that transcription MAPK Note various cascades. of MAPK tivation and PI3K/AKT JAK/STAT, including pathways OSMR kinase canonical of activation ετεροδιμερ 1. legendsFigure Figure endpoint Primary criteria sion/exclusion inclu- Key size Sample Dosing erie oteA-ffce kntruhCL7adCL2sgaig ntesi,CLA skin, the In signaling. CCL22 and CCL17 through skin AD-affected the to recruited CLA . β pcfi erimn fteaatrpoen H n H- aiiae hshrlto n ac- and phosphorylation facilitates SHP-2 and SHC proteins adapter the of recruitment specific + idn fI-1last eetrdmrzto,ctslcpopoyainadsubsequent and phosphorylation cytosolic dimerization, receptor to leads IL-31 of Binding . T H el r bnatalre-ecieTclsi h iclto fA ainsadare and patients AD of circulation the in cells T allergen-reactive abundant are cells 2 IgG2 humanized CIM331; (CD14152; Nemolizumab -0) k16 wk 0-100), (range VAS % Mean pruritus severe or moderate with AD size) target (204 PbO), (72 143 = N subcutaneous Q4W, mg 60 κ ? iue2 lutaindpcigteeet fI-1i tpcdermatitis atopic in IL-31 of effects the depicting Illustration 2. Figure Δ Λ3 ινλν ι τ οντ Λ1ΑΟΜβρςπο η- ρεςεπτορ ΙΛ31ΡΑ/ΟΣΜΡβ ςογνατε ιτς vια σιγναλινγ ΙΛ-31 + T IgG2 humanized CIM331; (CD14152; Nemolizumab k4; wk data, observed and MI LOCF, using score NRS % pruritus months, 6 [?] PN of diagnosis Clinical (57 226 = N PbO) (34 70 = N subcutaneous 8, wk to up Q4W 0.5mg/kg H Δ el otest fiflmain utrn edaki loop feedback-in a nurturing inflammation, of site the to cells 2 pruritus κ ? β- iue3 L3 ucini uoa Sites. Mucosal in Function IL-31 3. Figure xrsigctnossnoynre,int muecells immune innate nerves, sensory cutaneous expressing 17 β IgG2 humanized CIM331; (CD14152; Nemolizumab 24 % years 2 [?] AD Chronic PbO) subcutaneous 20, wk to up Q4W mg 90 30, 10, Δ xrsinrsligi togrreceptiveness stronger in resulting expression AI wk EASI, κ ? IgG2 humanized CIM331; (CD14152; Nemolizumab 12 % of AD AD Pruritic size) target 131 (191 = n B: Pt size); target 216 (264 = n A: Pt 52 wk above, B: Pt 12 Q8W,wk mg/kg 2.0 or Q4W, mg/kg or 2.0 0.5, 0.1, A: Pt Δ β A,wk VAS, κ muoeciiyhas immunoreactivity ? + T H el secrete cells 2 β otyin mostly IgG2 humanized CIM331; (CD14152; Nemolizumab AE of Assessment severity greater or moderate PbO) (9 = 36 n C: (6 Pt 24 PbO); = n B: Pt PbO); (14 n 56 A: = Pt 145 = N subcutaneous dose, single mg/kg, 3.0 1.0, 0.3, 0.1, 0.03, 0.01, 0.003, κ ? Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 18 Posted on Authorea 27 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160648038.83494811/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 19