Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV corneum (SC) is largely responsible for the barrier fun barrier the for responsible largely is (SC) corneum the most superficial layer of the skin, of which epidermis, thethe stratum by exerted is skin the of function barrier This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta 1 somatosensory sensation of itch, especially chronic itch the with associated closely is and surface, fissured and Dry skinischaracterized by ascaly, rough,cracked, DRY SKIN excessive waterlossandleadstoskindryness(1,2). of water in the SC. Impaired skin barrier integrity causes moisturizing factor, which has a key role in the absorption barrier against diffusion of water across the SC, and natural of SC humidity: intercellular lipids, which form the main ction. There are 2 elements important for the maintenance S Japan. E-mail:[email protected] Tomioka,279-0021, 2-1-1 Chiba Urayasu,Medicine, of School Graduate tute for Environmental and Gender Specific Medicine, Juntendo University Corr: Acta DermVenereol 2020;100:adv00024. Accepted Oct15,2019;PublishedJan9,2020 mouse model. Key words: tic strategiesforitchindryskinconditions. theupdatedpathogenesissummarizes andtherapeu havethusfor itching beendeveloped. Thisreview and sensitization of Several itch. thera­ and non-neuronal cellsintheinitiation, modulation, been acquiredinto the neurones interplay between a histamine-independentpathway.Newinsights have thehypothesissupporting is itch that dryskin-induced kines, areresponsible for itch and its hypersensitivity, ceptor family, transient receptor potential, and chemo and mas-related receptors,G e.g. protein-coupled re by water model have revealed that many mediators studies using Animal the acetone and ether followed is amixture of acetone andetherfollowed bywater. ofvestigate itch mechanisms associated with dry skin Catharina Mechanisms andManagementofItchinDrySkin and treatments. One ofthe basicmouseand treatments. models to in as kidney diseases, with an unclear pathomechanism as atopic dermatitis,such andsystemicdisorders,such accompanies pathological conditions, dryskin-based Chronic itch is a burdensome clinical problem that often Juntendo University Graduate School of Medicine, and Journal Compilation ©2020ActaDermato-Venereologica. Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender Specific Medicine, Specific Gender and Environmental for Institute (JIRC), Center Research Itch Juntendo logical barrieragainsttheexternalenvironment. The kin, the body’s largest organ, serves as a first physio Mitsutoshi Tominaga, Juntendo Itch Research Center (JIRC), Insti- Sagita MONIAGA dry skin; hypersensitivity; itch; sensory neuron; 1 , Mitsutoshi TOMINAGA Centenary theme section:ITCHANDPRURITIC DISORDERS peutic options 3 Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan REVIEW ARTICLE 1,2 and Kenji TAKAMORI ------are notfullyeffective inmanydermatologicalandsyste levels. All of these factors may lead to itch induction (10). sebaceous and sweat glands; and (v ( and intercellular lipid matrix changes; (ii ) pH variations; terations inthebarrierfunction ofSC,includingcellular skin changesintheelderlyarerelatedtoxerosis:(i ≥ aged individuals of 50% over conditions in the aged population worldwide (8), affecting skin dry prevalent most the of one is Xerosis Aged skin. Disease-related dryskin comfortable, but also affect patients un psychologically (7). physically only not are skin dry of manifestations clinical and signs The (1). used commonly are pH and hydration, SC (TEWL), loss water transepidermal tion, as filaggrin mutations (1, 5, 6). To assess skin barrier func exposure, temperature, humidity, and genetic factors, such which can be caused by environmental factors, such as sun barrier,skin the of function impaired is skin dry of tion (histamine-independent) itch (2). The underlying condi dry skin is an important feature of antihistamine-resistant mic diseasescharacterizedbydryskin,suggestingthat however, antihistamines (histamine H diseases (CLD),anddiabetesmellitus(DM)(4). such aschronickidneydisease(CKD),liver diseases, systemic pruritic in manifestation cutaneous common a is and psoriasis, and (AD), dermatitis atopic clinical manifestationofdermatoses,suchasxerosis, common most the is itch chronic with skin Dry (3). activity of (iv) reducedactivityof proteases; SC in alterations iii) py, phospholipids, antioxidants, and emollients. for itchinghave thusbeen developed, suchasphotothera and central nervous system. Several therapeutic options itch signallingamong theskinnervous system, skincells, kinds of mediators, receptors, and channels are involved in to be the primary cause of itch induced by dry skin. Many ney diseases. A decline in skin barrier function is thought conditions, such as xerosis, atopic dermatitis, liver and kid 6 weeks, often accompanies pathological dry skin-based treatments are unclear. Chronic itch, which lasts more than life, and for which the pathomechanism and appropriate Itch isan unpleasant sensation thatmay disturbquality of SIGNIFICANCE Histamine is a well-known substance that induces itch; 1–3 Acta DermVenereol 2020;100: adv00024 2 Anti-aging SkinResearchLaboratory, doi: 10.2340/00015555-3344 65 years (9). Multiple Multiple (9). years 65 ) decreased oestrogen 1 -receptor blockers) ) al - - ­ - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders clinically of apparent dry skin, patients with diabetes absence have the in Even DM. with patients in activity reduced hydration of the SC and reduced sebaceous gland a by supported are observations Clinical (21). pruritus and skin, dry infection, cutaneous e.g. DM, 2 type and 1 type both in disorders of spectrum broad a prise reflect itsdegreeinpatientswithCLD(20). opioids correlates with the severity of pruritus and may recently that the plasma dynorphin A level of endogenous ids, histamine, serotonin, and steroids (19). We reported may be involved, including bile salts, endogenous opio of 40.3% (18). Several potential itch-causing substances stood and often refractory to treatment, with a prevalence always correlatewithpruritus(17). bilayer abnormalities,anddrynessoftheskin,donot lipid skin, the of hydration of degree the as such skin, objective measurementsofthebarrierfunction suggested that dry skin can cause itch been in has CKD; It however, (16). patients uraemic in skin dry for part, in least at account, may glands sweat eccrine of lities abnorma functional The (15). (45%) subjects dialysis stages ofCKD,butit is morefrequentlydiagnosedin CLD, and DM (4). Skin dryness may appear at different manifestation in pruritic internal diseases, such as CKD, Systemic diseases. states, especiallyinacuteandchronicphases. intraepidermal nerves fluctuate in different skin disease of properties functional and density,structure, the that is possibility Another possible. is nerves of sprouting ment membrane were reduced, increased intraepidermal base the crossing nerves the although that, speculated nerves crossingthebasementmembrane. The authors epidermis, the observed as in a decreased hyperinnervation number of to cutaneous related not was it but AD, as such pruritus, chronic with patients in hyperesthesia nerve elongationandsproutingin AD (13). a nerve repulsion factor (NRF)), are related to this aberrant elongation factors (NEFs), and semaphorin 3A (Sema3A, amphiregulin (AR), and artemin (ARTN), which are nerve cause of skin hyperesthesia. Nerve growth factor (NGF), SC, due to drying and inflammation, is considered the to bea underneath immediately to epidermis the in nerve as such inflammation, sensory the of Elongation (5). AD an abnormalincreaseinsensitivitytostimuli)occurs cycle”. Skin hyperesthesia (a skin condition that involves matitis (12). This vicious cycle is called the “itch-scratch the affected areaisscratched,thenfurtheraggravatesder induce itchmainlybyactingonthesensorynerves,and Pruritogens 11). (5, area affected the from released are mediators, chemical and cytokines as such pruritogens, the skin barrier, such as AD and psoriasis. In these diseases, of dysfunction by characterized dermatoses in symptom diseases. skin Inflammatory 10 Skin disorders are common complications and com and complications common are disorders Skin The pathogenesis of pruritus in CLD is poorly under More recently, Pogatzki-Zahn et al. (14) reported skin C. S.Moniagaetal. Dry skinisalsoacommoncutaneous Dry skin itch is a common Dry skinitchisacommon ------the AEW-treated mice had marked epidermal hyperpla epidermal the marked AEW-treatedhad mice that showed analysis histopathological The treatment. was hydration SC and increased, consecutive days. TEWL and scratching behaviour were 5–7 for anaesthesia ether under daily twice performed were Treatmentss. 30 for area same the on placed was water distilled with soaked cotton treatment, AE after (1:1) was placed on the shaved area for 15 s. Immediately dermis (26, 27). Overall, the AEW treatment produces produces treatment AEW the Overall, 27). (26, dermis epidermis, but no infiltration of inflammatory cells in the sia, parakeratosis, and infiltration of nerve fibres into the cotton (2 start of the experiment. To disrupt the cutaneous barrier, over the rostral part of the back at least 3 days before the of dry skin-induced itch (26). The hair of mice was shaved one of the most well-known mouse models for the study skin model with itch). The AEW-treated mouse model is dry (chronic model (AEW)-treated Acetone/ether/water important factor for the regulation of itch in dry skin (3). C). The increase in intraepidermal nerve fibres may be an penetration of nerve fibres into the epidermis (Fig. 1B and decreased (Tominaga et al., unpublished data) before the was expression growth) nerve inhibits (which Sema3A but (3), increased was growth) nerve promote (which we found that the expression of epidermal NGF and AR in nerve fibre density in the epidermis (Fig.1A). Of note, the acetone-treated mice, although there was an increase in observed were hyperplasia epidermal or behaviours scratching No permeability. barrier cutaneous altered mice manifestthecharacteristicsofdryskinandhave acetone-treated the Thus, treatment. the after h 48 by normal to returned which treatment, after hour first the increase in TEWL and a decrease rapid in SC a hydration during displayed mice acetone-treated that found We from mast cells in the skin of acetone-treated mice (25). levels (3, 24). Others observed the release of histamine mRNAthese in increase the inhibited treatment acetone of the barrier immediately following barrier disruption by restoration artificial the and epidermis, the in increased were expression, gene factors, suchasNGFandARTN innervation-related intraepidermal that demonstrated treated withsterilewater(3,24). balls for 5 min. In the control group, the shaved area was The shaved area was treated with acetone-soaked cotton part of the back at least 3 days before acetone treatment. rostral the over shaved is mice of hair The application. itch). no with model skin dry (acute model Acetone-treated Dry skinmousemodels having generalizedpruritus(23). of probability higher a in result to reported were levels glucose postprandial Higher (21). neuropathy diabetic common in patients with diabetes who have dry skin or an impaired desquamation process (22). Pruritus is more Analyses of experimental animals treated with acetone One mousemodeltoinducedryskinusesacetone × 2 cm) soaked in a mixture of acetone and ether 2 cm)soakedinamixtureofacetoneandether decreased, under this decreased, underthis - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV due toEFA deficiency. HR-AD causes deterioration of the skin barrier function position of epidermal intercellular lipids (32). Therefore, changes inceramides,and reduced elaborationandde structural to due function barrier skin depress to ported EFA(31). skin re dry was of deficiency symptoms the (EFA)-deficient diet. Feeding HR-AD with EFA inhibits acid fatty essential an is HR-AD that revealed analysis composition Lipid (30). observed are IgE serum and epidermal hyperplasia, and increase in circulating T cells TEWL, and prolonged scratching bout duration. Marked by a decrease in skin water-holding capacity, increase in mice exhibited severe dry skin symptoms accompanied mouse models. Mice were fed HR-AD for 48 days. These diet (HR-AD) is one of the dry skin-based experimental Special diet food model. (27, 29),asdescribedlaterinthisreview. a greater than normal duration and/or magnitude of itch) ceptive state, in which a normally pruritic stimulus elicits non-pruriceptive) and hyperknesis (the abnormal pruri ching behaviourevokedbyastimulusthatisnormally W/W (WBB6F1- mice cell-deficient mast between scratching was no apparent difference in AEW-induced spontaneous (28). humans in There conditions itchy chronic many in present symptoms skin dry the recapitulate which (26), changes in gene expression in sensory nerves and the skin marked skinbarrierdysfunction,robustscratching,and epidermis anddermis(basementmembrane), respectively. The basement membrane in panel B was stained with an anti-nidogen antibody (red Nuclei are counterstained by DAPI (blue). Thebroken lines inpanel A indicate the border between the epidermis and dermis (basement membrane). Sema3A (green an anti-PGP9.5 antibody. (B, C)Maximum expression of NGF (green dry skinmodelmice. Fig. 1. Alterations in nerve fibre distribution, and nerve growth factor (NGF) and Sema3A expression in the epidermis of acetone-treated This dryskinmodelalsoexhibitsalloknesis(scrat V ) andnormallitter-mates (WBB6F1- ) was decreased 24 h after acetone treatment (C). These expression levels gradually returned to normal by 168 h after the treatment. (A) Sequential alteration of intraepidermal nerve growth in acetone-treated mice was examined by immunohistochemistry using HR-1 hairless mice fed a special +/+ ) (26). ) (26). Arrowheads ) was noted 16–24 h after the treatment (B). In contrast, the expression level of indicateepidermalnerve fibres(green).Scalebars:15μm. - - - - Using mensional extracellular matrix (ECM) barriers (Fig. 2). 3-di the penetrate to cones growth for MMPs several requires skin dry in growth nerve cutaneous of process MMP-8. The and (MMP)-2 metalloproteinase Matrix regulation ofitching(34). endothelial cells, and may be indirectly involved in the also acton keratinocytes, immunecells, and vascular tinocytes (5, 13). These axonal guidance molecules may and AR, and NRFs, such as Sema3A, produced by kera NGF,as such NEFs, of balance the by regulated ARTN The controlling mechanism of cutaneous nerve density is and AD (13), as well as in dry skin mice models (3, 33). xerosis senile as such diseases, dermatological pruritic with patients of skin the in observed been has density nerve intraepidermal increased An junctions. dermal most cutaneous nerve fibres terminate under dermoepi under terminate fibres nerve cutaneous most Nerve elongation and repulsion factors. In healthy skin, Sensory neurones resulting intheperceptionofitch(Fig.2). ascending sensory pathway to the somatosensory cortex, the through transmitted is potential action evoked The fibre afferents andthinlymyelinated Aδ-fibre afferents. C- unmyelinated e.g. afferents, sensory peripheral on receptors cognate their to substances itch-inducing The sensationofitchisgeneratedbythebinding MECHANISMS OFITCHINDRY SKIN ). White and models of ECM, we found that MMP-2 that found we ECM, of models vitro in Mechanisms andmanagementofitchindryskin broken lines indicate the skin surface and the border Theme issue: Itch and pruritic disorders 11 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders of consist fibres nerve peripheral epidermal elongated the in fibres. increase nerve An stimulate turn in which ferent cell populations in the different layers of the skin, dif with communicate to dermis the in nerves sensory by produced neuropeptides are (CGRP) peptide related Peptidergic fibres. Substance P (SP) and calcitonin gene- a reversesignallingpathwayfortheseevents(38). Sema3A stimulation of growing nerve fibres may provide signalling inhibits integrin-mediated adhesion signalling, long-distance axon extension (37). As class 3 semaphorin and efficient for necessary is signalling ECM-integrin ting that the coordinated activation of neurotrophin and be required for efficient nerve fibre penetration, sugges may fibres nerve growing the surrounding components ECM the to corresponding MMPs of up-regulation and by NGF and down-regulated by Sema3A. The selection upregulated were MMP-8 and MMP-2 of expression of levels The (36). dermis the within growth nerve in involved be to reported was fibres nerve by secreted MMP-8 addition, In (35). membrane basement the into penetration in functioned cone growth the on localized signalling, alongwithastrocytosisinthespinalcord.Moretreatmentsha itch in involved also are cluster) (NP C-fibres non-peptidergic the KCs, from released substances to addition In epidermis. the penetrate fibres nerve sensory more diseases, skin inflammatory accompanyingitch-scratchor skin the systemic dry in chronic cycle,as In such (C) phase. this in symptoms which leads to the penetration of nerve fibres into the basement membrane and their growth. Emollients and phospholipids are effective at(TSLP) and interleukin alleviating(IL)-33 released from KCs. NGF the also promotes matrix metalloproteinase (MMP)-2 and MMP-8 production in sensory nerve fibres, prominent and induces the elongation of cutaneous nerve fibres into the epidermis. This elongation may also be affectedDuring environmentalby stimuli inacute dry skin conditions, nerve growth factor (NGF), an epidermal nerve elongation factor (NEF) produced by KCs, is (B) thymic junction. stromal dermo-epidermal lymphopoietin the under fibres nerve cutaneous the maintains It dominant. is (KCs), keratinocytes by mainly produced (NRF) factor to thesomatosensory cortex in the brain through the spinal cord, resulting inthe recognition of itch. (A)Inhealthy skin,Sema3A, a nerve repulsion their respective receptors/channels expressed in peripheral sensory afferents. Electric signalsgenerated in the peripheral nerve endings are transmitted itch. The of dryskin-induced perception and management Fig. 2.Mechanisms of itch starts when endogenous and exogenous itch mediators activate 12 C. S.Moniagaetal. - - ve beenconfirmedtobebeneficialinthiscondition. sis of neurochemical criteria. The peptidergic neurones are out ( GRPR of development the for essential be to demonstrated was cord spinal the in Tlx3 factor response to multiple pruritogens (41). The transcription scratching the in reduction significant in resulted rones (GRPR) GRPreceptor of ablation Genetic rones. reported that Tlx3 conditional knock that conditional reported Tlx3 Huang etal.(43) subset of peptidergic of subset small a in expressed specifically and signals itch relays specifically that neurotransmitter a as characterized is the AEW model(39, 40). epidermal peptidergic nerve fibres, has been reported in represent usually which C-fibres, SP/CGRP-containing peptidergic and non-peptidergic subsets mainly on the ba into divided been have C-fibres fibers. Non-peptidergic chronic itchinthesemice. skin model, suggesting impairment of dry skin-induced dry the in controls with compared less much scratched DRG TrkA-lineagemost in expression The neuropeptide gastrin-releasing peptide (GRP) peptide gastrin-releasing neuropeptide The Tlx 3 F/F ; Nav1.8-Cre dorsal root ganglion (DRG) neu ganglion root dorsal mice specifically lost Tlx3 lost specifically mice + neurones) mice neurones(42). + neu - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV initiation andmaintenance of chronicitch(55). TRPA1-dependent. These genes play diverse roles in the whereas CCL27 and Tenascin C (TNC) are scratch- and cycle, itch-scratch the of independent are TRPA1,and require S100A9 and Slc9a3r1, lipocalin, CXCR2, tor recep chemokine IL-33, AQP3, changes: independent scratch- and scratch-dependent both regulates TRPA1 genes, disease human the Among skin. the in changes expressional and hyperplasia, epidermal scratching, the dry-skin-evoked phenotypes, including for required TRPA1functional is that found (55) al. et pruritogens, chloroquine and BAM8-22 (49, 54). Wilson itch behaviour downstream of 2 histamine-independent and activation neurone sensory e.g. itch, independent histamine- acute mediate to reported previously was (TRPA1)1 subfamily TRPAchannel member ion The sensors. cellular polymodal as known are channels TRP The (TRP) . family potential receptor Transient pH areinvolvedindryskin-relateditch. knockout mice (52), suggesting that fluctuations in skin (ASIC3) 3 channel ion acid-sensing in inhibited were The increases in expression of MrgprA3 and MrgprC11 (53). itch skin-related dry in functions MrgprA3 that ced chronic itch induced by AEW treatment, suggesting Moreover, the ablation of MrgprA3 dry skin model mice than in water-treated controls (52). in AEW-treatedhigher be to found MrgprC11was and (49–51). The expression of mRNAs encoding MrgprA3 cently suggestedtobeinvolvedinthetransmissionofitch re were and (TG), ganglia trigeminal and DRG the in are expressed only on small-diameter sensory neurones (48). MrgprA3, MrgprC11, and MrgprD in mice, which subfamilies: MrgprA, MrgprB, MrgprC, and MrgprD-G several into grouped be can mice in family Mrgpr The Mas-related G protein-coupled receptor family (Mrgpr). endogenous agonists of this receptor in chronic itch (27). for role a implicating PAR-2agonist, the to responses larger significantly exhibited mice AEW-treated from the dry skin area or systemically. In addition, DRG cells attenuated by a PAR-2 antibody either delivered locally to significantly was animals skin-treated dry in behaviour sidered involved in itch (27, 47). Spontaneous scratching CGRP not but fibres, intraepidermal non-peptidergic increased treatment AEW that reported and CGRP involvement in the AEW model, a recent study tin B4 (IB4) (44). On the contrary to previous reports of SP by the purinergic P2X3 receptor and the plant lectin isolec whereas non-peptidergic neurones are commonly labelled mostly marked by neuropeptides, including SP and CGRP, keratinocytes, mast cells, and macrophages, and are con other than PAR-3 are expressed in cutaneous nerve fibres, PAR-1,PAR-4.PAR-2,PARsPAR-3,members: and 4 of consist (PARs)PARsreceptors . Protease-activated imiquimod-induced psoriasismousemodel(46). the of behaviour itch in observed is as (45), itch skin dry that a specific subset of non-peptidergic fibres functionin + DRG neurones redu + fibres, suggesting suggesting fibres, AEW-evoked - - - - - a heat-sensitive cation channel that is selectively expres were previously associated with non-peptidergic noci non-peptidergic with associated previously were (including NP1-3), expressed cluster NP the third, The nociceptors. peptidergic with associated previously were which CGRP, and (Ntrk1) cluster (including PEP1-2), expressed SP (Tac1), TRKAPEP the second, The neurones. DRG myelinated with associated previously was and (Pvalb), parvalbumin (Nefh)and chain heavy neurofilament expresses which NF1-5), (including cluster NF the is cluster first The DRGs. lumbar mouse from neurones sensory of cells damentally distinct types of sensory neurones) in single reported 4 neuronal clusters (57) (further divided al. into 11et fun Usoskin neurones. sensory of clusters NP tion and/orenhancementofitchindryskin. induc the in involved partly channel. be also may This in the skin of AEW model mice due to expansion of this innervation density of TRPV1-expressing sensory fibres pain sensations (56). Yu et al. (28) reported an increased and DRG, which plays an important role in thermal and TG in neurones sensory primary of population a in sed revealed that TRPV4 is selectively expressed by epi by expressed selectively is TRPV4 that revealed (60) al. et Luo 59). (58, (5-HT) 5-hydroxytryptamine acute itch elicited by exogenously applied histamine in and involved be to reported was (TRPV4) 4 member V subfamily channel cation potential receptor Transient Keratinocytes related to the pathomechanism of dry skin-induced itch. new types and classification of neurones may be closely These (57). neurones NP3 engage may serotonin, and chronic states of inflammatory itch, as well as histamine to linked are which leukotrienes, cysteine and IL-31 as such mediators, and neurones, NP2 to tuned be may itch acute with associated histamine and chloroquine neurones, NP1 to tuned be may disorders cholestatic response profiles: lysophosphatidic acid associated with unique with neurones responsive itch of classes 3 least at of existence the support data their Thus, PEP2. and (Htr1f, receptors serotonin mine receptors (Hth1) were found in NP2 and NP3, Hista and NP3. in P2X3 of level low a and markers, Sst) Nts, and (Nppb, somatostatin and neurotensin, peptide, ( (Il31ra andOsmr)-cysteineleukotriene (IL)-31 interleukin and NP2, rones (Mrgpra3in andMrgprx1) neu chloroquine-responsive class, NP1 the in Lpar5) (Lpar3 and neurones acid–responsive lysophosphatidic detected They itch. inflammatory transduce and sense to likely is NP3 and itch, in function to reported were rones. Furthermore, NP1, NP2, and NP3 neuronal types described inadistinctsubclassofunmyelinatedneu (Th) andhasbeen hydroxylase tyrosine of expression distinct exhibited cluster, TH the fourth, The ceptors. Cysltr2)-responsive neurones, neuropeptides natriuretic TRP cation channel subfamily V member 1 (TRPV1) is Mechanisms andmanagementofitchindryskin Theme issue: Itch and pruritic disorders ) were found in NP3 in found were Htr2a) Mrgprd andP2rx3, which 13 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders 3 receptor chemokine motif C-X-C and (CXCL10) 10 ligand chemokine motif C-X-C that reported (68) al. et Qu (67). neuroinflammation disease-associated and transmission, synaptic development, neuronal cluding in conditions, pathological and physiological both under function its regulate they where system, nervous central the in expressed are Chemokines Chemokines. partly involvedintheinductionofitchdryskin(66). is system GRP/GRPR spinal the that suggest data These pathway. PI3Kγ the via itch transmit which afferents, is expressed by the central terminals of DRG nociceptive tenuated the scratching behaviour, suggesting that GRPR at route, systemic or intrathecal by inhibition PI3Kγ or related to itch. In a dry skin model of itch, is GRPR and blockade GPCRs of downstream activated is cascade, ling signal intracellular the in participate that kinases lipid a PI3Kγ, (41). behaviour scratching induce GRPIntrathecal cord. spinal the in sed to GRPR via acts tor (GRPR), a G Gastrin-releasing peptide system. The GRP and its recep Spinal cord of dryskinitself. by keratinocytes play an essential role in the mechanism ACD, it is highly possible that TSLP and IL-33 produced the close relationship between itchy-dry skin and AD or 33 production from keratinocytes (64, 65). Considering IL- promote tape-stripping, as such skin, the to trauma and AD, in noted that as such keratinocytes, to stress pruritus in this model. Studies revealed that hypo-osmotic present in primary sensory neurones and found to lead to functionally were skin) the innervate which neurones, this study, IL-33 and its receptor ST2 (expressed in DRG urushiol-challenged of skin the in In mice. model ACD released by keratinocytes is a key cytokine up-regulated robust itchbehaviours(62). on a subset of TRPA1-positive sensory neurones to trigger TSLP release from and keratinocytes, TSLP acts directly of regulator essential an as pathway signalling calcium ORAI1/NFAT the identified al. et Wilsonitch. promote to TSLP via neurones sensory cutaneous with directly communicate keratinocytes that reported further was it an important role in the development of AD (61). Of note, plays keratinocytes by produced (TSLP) lymphopoietin thecytokinethymicstromal 2 activationinkeratinocytes, Previously, we demonstrated that, possibly through PAR- neous diseasescharacterizedbydryskinandchronicitch. receptors in AEW asdownstreamsignalling. 5-HT signalling secondary to activation of distinct 5-HT mice. Moreover, TRPV4-dependent chronic itch requires of TRPV4 in keratinocytes reduced itch in AEW-treated dermal keratinocytes in mice. Lineage-specific deletion 14 reported as itch-specific signalling molecules and expres Liu et al. (63) also reported that IL-33 produced and produced IL-33 that reported also (63) al. et Liu cuta are (ACD) dermatitis contact allergic and AD C. S.Moniagaetal. αq -protein-coupled receptor (GPCR), were member of member of ------and TLR4 (70, 71), and their important roles, such as spi that primary sensory neurones express TLRs, e.g. TLR3 produced after tissue injury. There is increasing evidence via recognitionofexogenousandendogenousligands proteins that can mediate innate and adaptive immunity Toll-like receptors (TLR). TLR are type I transmembrane induced itch(69). an essential role in the pathogenesis of chronic dry skin- expressing astrocytes in the spinal dorsal horn. dorsal spinal the in astrocytes expressing TLR4 TLR4 mRNA and increased TLR4 expression in GFAP- AEW mouse model exhibited persistent upregulation of nal cord glial activation in neuropathic pain (72, 73). The CXCR3 tion, AEW-inducedin reduced was activation astrocyte (78). Zeta chain-associated protein kinase 70 (ZAP70), 70 kinase protein chain-associated Zeta (78). pruritus skin dry in function to reported was pathway Zeta chain-associated protein kinase 70. TheT-cell signal Others central mechanisms(77). expression of chronic itch in dry skin via peripheral and full the for required partly is signalling TNF-α/TNFR1 only in the spinal cord. Thus, these expression findings suggest that TNFR1 and cord, spinal and DRG, skin, mice. AEW treatment induced TNF-α expression in the (TNF-α antagonist), and in TNFR1/R2 double-knockout thalidomide (TNF-α-synthesis inhibitor) of administration the by by induced reduced AEWwas itch skin Dry (76). TNFR2 and/or TNFR1 receptors, its via pain chronic and cord spinal the in plasticity synaptic regulating in role central a play to reported was TNF-α (75). modulators and/or mediators itch key suggests thatcytokinesandchemokinesalsoserveas Tumourevidence necrosisEmergingfactor-α (TNF-α). alloknesis (74). and itch chronic underlie may which astrogliosis, and activation astrocyte spinal for important is signalling and alloknesis. These findings suggest that spinal TLR4 a suppressed RS), antagonist, TLR4 AEW-induceditch lipopolysaccharide from of injection Intrathecal scratching. prevent to neck the induced astrogliosis was abrogated by AEW-placing collarsbecause on astrogliosis spinal in role essential an ced AEW-induced itch and alloknesis. Scratching plays redu L-α-aminoadipate inhibitor astroglial of injection liosis (GFAP upregulation) in the spinal cord. Intrathecal fewer scratching responses than control mice. In addi In mice. control than responses scratching fewer CXCL10 in the spinal cord, and CXCR3 and cord, spinal the in CXCL10 and CXCR3 of expression the induced AEWtreatment note, Of CXCR3. neuronal through neurones DRG cutaneous of subset a activates directly CXCL10 and model, an ACD in DRG the in increased are (CXCR3) AEW. This model also induced TLR4-dependent astrog alloknesis, a touch-elicited itch in wild-type mice, after mice exhibitedsubstantialreductionsinscratchingand –/– mice, suggesting that the spinal CXCR3 plays Rhodobacter sphaeroides (LPS- and etanercept –/– micehad –/– - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV mice exhibited significantly larger responses to the PAR- AEW-treated from cells DRG Moreover, conditions. skin dry PAR-2under 5-HTa and of agonist injections the numberofscratchingbouts evokedbyintradermal to itchprovocationoranactivelyitchyskinlesion(88). secondary when mechanism central a through fibres Aδ ctate stimuli (87). Hyperknesis may be mediated by type-I type of afferents mediate the mild itch resulting from pun hyperknesis are not clear, and it remains unknown which of mechanisms The (86). stimulus given a to threshold itch lowered or stimuli itch-provoking normally to itch enhanced is there which in state the encompassing term umbrella an as proposed was “hyperknesis” term The Hyperknesis peripheral andcentralmechanisms. both via presumably (85), nalfurafine agonist κ-opioid the and (26), naltrexone and naloxone as such nists, antago μ-opioid of injection subcutaneous by pressed sup significantly was treatment AEWafter scratching Spontaneous (84). (VAS)score scale analogue visual the κ-opioid system, concomitant with a decrease in the therapy downregulated the μ-opioid system and restored patients with AD, and that psoralen-ultraviolet A (PUVA) κ-opioid system was downregulated in the epidermis of pressive effects (18, 83). We previously reported that the activation of κ-opioid receptors is believed to have sup μ-opioid receptors is thought to induce pruritus, whereas of Activation FQ). nociceptin/orphanin for receptor (a nociception and enkephalins), for receptor (a δ-type β-endorphins), κ-type (KOR, for a receptor receptor for dynorphins), a (MOR, μ-type receptors, opioid of pes in TLR3 was TLR3-dependent. Spontaneous itch was eliminated which skin, the in upregulation NGF marked induced the skin, but not in the DRGs. Moreover, AEW treatment elicited a marked 25-fold increase in TLR3 expression in sed by mast cells and keratinocytes (81). AEW treatment mice. expres in also DRG is and TLR3 nerves sensory by expressed is and signalling, itch murine in receptor Toll-like receptor 3. TLR3 was found to be an important increased secretionofIL-2andNGF(80). in dry skin in pruritus in elderly people, probably due to involved is ZAP70 increased that revealed study This old AEW mice compared with 5-month-old AEW mice. addition to the secretion of IL-2 and NGF in 22-month- mice. ZAP70 expression was significantly increased, in AEW 5-month-old with compared scratching neous sponta increased exhibited mice AEW 22-month-old mote NGF secretion in skin (79). After AEW treatment, as a T-cell receptor, may induce IL-2 secretion and pro . Previous studies have identified 4 major ty major 4 identified have studies Previous Opioids. of chronicitch(82). dry skin are important for the induction and sensitization Akiyama et al. (27) reported a significant increase in increase significant a reported (27) al. et Akiyama –/– mice. Thus, TLR3 and its upregulation in the ------dry skinitch(29). chronic of model animal this in alloknesis of presence the suggesting mice, in treatment AEW of region a of mulation elicited scratching when delivered at the edge sti mechanical Innocuous cord. spinal the in neurones hold mechanoreceptors excites sensitized itch-signalling central mechanism in which the activation of low-thres as itchy skin or alloknesis (90). Alloknesis may reflect a intradermal injection of histamine, a phenomenon known the by induced itch experimental of site a surrounding skin normal of region a within delivered when itch elicit to reported were stimuli mechanical Innocuous Alloknesis pathways. itch-signalling of sensitization the with consistent is which hyperknesis, reflects This skin. itchy chronic in enhanced is agonists, PAR-2 and 5-HT as such gens, highlight the importance of itch-responsive amygdala itch-responsive of importance the highlight population of the amygdala in adult mice. These results like behaviourandincreased neuroneactivityinasub acute itchstimuli,suchas histamine, inducedanxiety- of anxiety (95). Recently, Sanders et al. (96) reported that in AEW-treated micewithchronicitch. of the hypothalamic pituitary adrenal (HPA) axis function behaviour. They also demonstrated primary disturbance haviours were significantly related to the itch-associated chronic itch evolves over time. The mood impairment be AEW treatment, suggesting that mood impairment due to after weeks 3–4 phenotypes depression-like and weeks 2–3 symptoms anxiety-like developed mice AEWthat psychiatric illnesses (70%) (93). Zhao et al. (94) reported with high incidences of suicidal motivation (21.1%) and chological burden produced by chronic itch was reported psy The (7). patients dermatological in predominantly ment of mood disorders, such as anxiety and develop depression, the with correlated clinically is itch Chronic ITCH OFDRY SKIN AND ANXIETY critical inmodulatingtheconversionoftouchtoitch. that cutaneous Piezo2 channel-Merkel cell signalling is tected againstalloknesisindryskin. These datasuggest alloknesis. Chemogenetic activation of Merkel cells pro associated mechanosensitive Piezo2 channels produced cells. Targeted geneticdeletionofMerkelcellsandits Merkel of loss a with associated is skin dry in loknesis adapting afferents (91). Feng et al. (92) reported that al ported to make “synapse-like” contacts with type I slowly This implies that acute itch elicited by certain prurito certain by elicited itch acute that implies This (89). reported been have model this in agonist PAR-2 intradermal to neurones horn dorsal superficial lumbar 2 agonist and 5-HT. Furthermore, enhanced responses of Merkel cells, the touch receptors in the skin, were re The amygdala is the key brain region for the generation The amygdala is the key brain region for the generation Mechanisms andmanagementofitchindryskin Theme issue: Itch and pruritic disorders 15 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV and H cream, ontoacetone-induceddryskinreducedthenum of emollients, e.g. hydrophilic petrolatum and heparinoid In our previous study, immediate and delayed application Emollients innervation indryskinconditions. partly improve skin barrier function and epidermal hyper may antihistamines however, histamine-independent; be to thought is conditions, AEW-induceditch pruritic intractable many to Similar (99). treatment acetone by disrupted was barrier skin whose mice in hyperplasia downregulated NEFs (NGF and (NGF NEFs ARTN)downregulated mRNA nor in with AD patients (97). We in pruritus recently demonstrated for that bepotastine beneficial be to reported were Theme issue: Itch and pruritic disorders Table I.Therapiesfordryskin-induceditch contained which (TSG), lotion moisturizing gel-like of application addition, In (33). skin mouse the in levels NGF and fibres nerve intraepidermal penetrated of ber H of application topical that found nerve density in dry skin conditions (98). epidermal Another with report associated itch controlling for fective H histamine the via mechanisms NF-kB-dependent and/or AP-1- of activity transcription the by mediated mal human epidermal keratinocytes. The alteration was Second-generation H Antihistamines Table I). and 2 (Fig. itch skin-induced dry of management the models were reported, there have been many studies on Since themechanismsofdryskin-induceditchinanimal MANAGEMENT OFDRY SKIN-INDUCED ITCH tions duetodryskin. behaviour,condi itch chronic to apply also may which neurones in the regulation ofitch-related effects and 16 that second-generationH evidence therapeutic provide results These receptor. Second generation of H1-antihistamines, e.g. bepotastine Adjunctive treatment Fish oil Antioxidants Collagen tripeptide μ-receptor antagonist& κ-opioidagonist Neurotropin Systemic treatment • Excimer lamp • • Phototherapy Film dressings • hydrophilic petrolatum, heparinoid cream, gel-like moisturizing lotion Emollients Topical treatment Therapeutic method Narrowband ultraviolet B Psoralen ultraviolet A 2 (famotidine)-antihistamines prevented epidermal C. S.Moniagaetal. 1 -antihistamines (e.g. bepotastine) (e.g. -antihistamines 1 -antihistamines maybeef 1 (diphenhydramine) • Reduction in nerve elongation factors and epidermal hyperplasia • Improvement of skin barrier function • Inhibitionof oxidative stress in theperiphery • Reduction in epidermal nerve density, normalization of axon-guidance factors • μ-receptorantagonist and κ-opioid agonist in the central nervous system • Reduction in epidermal nerve density • Induction of cutaneousnerve degeneration  • Normalization of expression levels of nerve elongationfactors and nerve repulsion factors • Prevention of mechanical stimulus • Reduction in epidermal nerve density • Reduction in epidermal nerve density Mechanisms ofantipruriticeffects Reduction in epidermal nerve density ­ - - - - 1

epidermis (104). the in Sema3A and NGF of expression abnormal the in this model. PUVA+BV and NB-UVB also normalized cantly reduced the intraepidermal nerve growth induced signifi treatments lamp excimer and NB-UVB, (BV), model, PUVA, PUVA+betamethasone valerate ointment (103). Furthermore, in the acetone induced-dry skin mice reduces epidermal hyperinnervation in patients with AD PUVAstudy,therapy previous our In (102). psoriasis and with (101) patients AD in pruritus chronic of ment skin-related cutaneous or systemic diseases (106, 107). skin-related cutaneousorsystemicdiseases(106,107). κ-opioid receptor agonists were found to inhibit itch in dry agonists (85). Clinically, μ-opioid receptor antagonists and μ-opioid receptor antagonists (26) and κ-opioid receptor Dry skin-related itch in animal models was suppressed by Opioids degeneration andreducedDNA damage(105). nerve epidermal of induction the to due are COF with irradiation lamp excimer of effects antipruritic the that acetone-induced dryskinmousemodel. This suggests butane pyrimidine dimer, a DNA damage marker, in the cyclo of production the and hyperinnervation reduced wavelengths, cytotoxic decreasing thus lamp, the to monstrated that attaching a cut-off excimer these in changes degenerative induced nerve of tion ultraviolet B (NB-UVB), are efficacious in the treat the in efficacious are (NB-UVB), B ultraviolet narrowband- PUVAand as such therapies, UV-based Phototherapy inhibition ofepidermalhyperinnervation(100). by chronicdryskinthroughamechanisminvolvingthe induced itch attenuates TSG of application topical that suggests This mice. AEW-treated of epidermis the in nerve fibres, and induced higher expression of Sema3A and agar, reduced the number of infiltrated intraepidermal paraben, propyl paraben, methyl urea, glycerin, water, In addition, we reported that excimer lamp irradia lamp excimer that reported we addition, In bres formed by cultured DRG neurones DRG cultured by formed fibres bres. We de We fibres. filter (COF) - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV in acetone-treated mice was reduced by the intraperito the by reduced was mice acetone-treated in vitro(111). Moreover,density nerve intraepidermal the neurones in DRG of outgrowth neurite NGF-induced (110).study inhibits We sample neurotropin that found small open-label, multicentre, a in pruritus resistant was reported as an effective treatment for antihistamine- virus, vaccinia with inoculated rabbits of skin inflamed the from isolated extract non-protein a Neurotropin, Neurotropin receptors (109). μ-opioid the to affinity high effectsand antagonistic its treatment option for opioid-induced pruritus because of systematic review suggested that nalbuphine is a superior clinically indicated for moderate to severe pain (108). A κ-opioid receptors agonist-μ-opioid receptors antagonist, in theepidermis,addition toreducingpruritus(120). improves dry skin and normalizes axon-guidance factors lagen tripeptide to acetone-induced dry skin model mice in murineskin vivo (119). Oral administration of col acid production in human dermal fibroblasts many biologicaleffects, such asenhancinghyaluronic have to known is that fraction collagen allergenic low non-antigenic, purified, highly a is tripeptide Collagen Collagen tripeptide itch by reducing intraepidermal nerve fibre density (118). skin-induced dry of alleviation and/or prevention the for dry skin. Thus, dietary MPLs may have beneficial effects acetone-induced of model mouse a in Sema3Alevel the dermis by reducing epidermal NGF levels and increasing MPLs attenuate the penetration of nerve fibres dietary into thethat epi reported we Recently, (117). model mouse HR-AD the in function barrier skin (116),improved and mice HR-1 hairless normal in hydration SC increased as beneficial effects on epidermal functions (116, 117), such have to reported been have sphingomyelin milk-derived improved scratchingbehaviour(115). dry skin rat model restored the skin barrier defects and a well-known source of n-3 PUFA, in an acetone-induced barrier function (113, 114). Supplementation of fish oil, skin the regulates skin the within content their because homoeostasis skin in role essential an play metabolites dies suggested that n-3 PUFA and related monohydroxy (n-3) polyunsaturated fatty acids (PUFA). Previous stu 3 omega representative are 6n-3) 22: (DHA, acid enoic Eicosapentaenoic acid (EPA, 20: 5n-3) and docosahexa Phospholipids expression ofSema3A intheepidermis(112). neal administration of neurotropin, probably through the Nalbuphine is a synthetic opioid analgesic, a mix of mix a analgesic, opioid synthetic a is Nalbuphine Dietary milk-derived phospholipids (MPLs) and (MPLs) phospholipids milk-derived Dietary in vitro and - - - - - found that the level of NGF in others the mouse epidermis sig and we this, with Consistent (124). skin the of hypersensitivity itch reduce may dressings Film mice. tion and alloknesis in the AEW-induced dry skin model to contamination, alleviated the epidermal hyperinnerva an appropriately moist environment and act as a barrier dressings, which are used for wound treatment to provide film of application the that reported recently,we More Film dressings on dryskin-induceditch. tert-butyl-a-phenylnitrone, may have therapeutic effects N- and N-acetyl-L-cysteine as such antioxidants, Thus, and suppression of p-ERK activation in the spinal cord. skin) (affected periphery the in stress oxidative of tion The authorshavenoconflicts of interest todeclare. from MEXT (S1311011), andKAKENHI(18K07396). Research Foundation Grant-aided Project for Private Universities Japan Society for the Promotion of Science (18F18410), Strategic This work was partly supported by Research Fellowship from the ACKNOWLEDGEMENTS improve thequalityoflifepatients. complex interactions and to develop antipruritic drugs to Continued studies are required to better understand these channels. TRP and cytokines, TLR, Mrgprs, including nervous system,skincells,andcentralsystems, channels areinvolvedinitchsignallingamongtheskin and receptors, mediators, of kinds Many skin. dry of the in model mouse well-known most AEWthe model, the primary cause of dry skin-induced itch, as observed ment. A decline in skin barrier function is thought to be mechanisms ofdryskin-induceditchanditsmanage the regarding knowledge recent presented review This CONCLUSION the skin. induced by barrier disruption and mechanical stimuli to skin moisturization prevents epidermal hyper­ disruption by tape-stripping or acetone. This suggests that a vapour-impermeable membrane (24) after skin barrier nificantly decreased by occlusion with emollients (33) or bouts of AEW-treated mice, possibly through the inhibi were systematically effective in reducing the scratching in mice (122). Zhou et al. (123) reported that antioxidants histamine-independent itch via the activation of TRPA1 induce to demonstrated were Oxidants (121). failure renal chronic and psoriasis, AD, including diseases, systemic and skin itch-related of pathogenesis the in role a play to proposed been long has stress Oxidative Antioxidants Mechanisms andmanagementofitchindryskin Theme issue: Itch and pruritic disorders innervation innervation 17 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders REFERENCES 18 23. 22. 21. 20. 19. 18. 17. 16. 15. 14. 13. 12. 11. 10. 4. 3. 2. 1. 9. 8. 7. 6. 5. agents and itch mechanisms independent of mast-cell his Kuraishi Y. assessmentofantipruritic Methodsforpreclinical treated mice. J Dermatol Sci2007; 48: 103–111. Intraepidermal nerve fibers increase in dry skin of acetone- Tominaga M, Ozawa S, Tengara S, Ogawa H, Takamori K. Dermatol 2017;1. and treatments of dry skin induced itch. 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