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JOURNAL OF BIOLOGICAL REGULATORS & HOMEOSTATIC AGENTS Vol. 33, no. 1, 1-6 (2019) EDITORIAL ,17(5/(8.,1)$0,/<&<72.,1(6$1'0$67&(//6 $&7,9$7,21$1',1+,%,7,21

C.E. GALLENGA 1, F. PANDOLFI , A. CARAFFA 3, S.K. KRITAS 4, G. RONCONI 5, E. TONIATO 6, S. MARTINOTTI 6 and P. CONTI 

1Department of Biomedical Sciences and Specialist Surgery, Section of Ophthalmology, University of Ferrara, Italy; 2’ La Cattolica ‘ University, Rome, Italy; 3School of Pharmacy, University of Camerino, Camerino, Italy; 4Microbiology and Infectious Diseases, Aristotle University of Thessaloniki, Macedonia, Greece; 5UOS Clinica dei Pazienti del Territorio, Policlinico Gemelli, Rome, Italy; 6Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy; 7Immunology, Postgraduate Medical School, University of Chieti-Pescara, Chieti, Italy

Received Decmber 2, 2018 – Accepted January 9, 2019

7KLVHGLWRULDOIRFXVHVRQUHFHQWSURJUHVVUHSRUWVRQPDVWFHOOV 0&V DQG,/IDPLO\F\WRNLQHVLQWKH G\QDPLFVRILQÀDPPDWLRQ0&VDUHFHOOVRIKDHPDWRSRLHWLFGHULYDWLRQWKDWPDWXUHDQGUHVLGHLQDOPRVW DOOYDVFXODUL]HGWLVVXHV0&VDUHDSRWHQWLDOVRXUFHRIF\WRNLQHVDQGFKHPRNLQHVZKLFKSDUWLFLSDWHLQ DOOHUJLF UHDFWLRQV DQG LQÀDPPDWLRQ$FWLYDWHG 0&V VHFUHWH D QXPEHU RI FRPSRXQGV LQFOXGLQJ SUR LQÀDPPDWRU\F\WRNLQHV0&V FDQEHDFWLYDWHGE\,J(WKURXJK LWVUHFHSWRU)FH5,EXW DOVRE\7ROO OLNH UHFHSWRUV 7KH\ FDQ EH D WDUJHW IRU ERWK SURLQÀDPPDWRU\ DQG DQWLLQÀDPPDWRU\ F\WRNLQHV ,/DFWLYDWHV0&VWRUHOHDVHLQÀDPPDWRU\FKHPLFDOPHGLDWRUVDQGF\WRNLQHVFKHPRNLQHVDQHIIHFW ZKLFKFDQEHSRWHQWLDOO\LQKLELWHGE\,/,QDGGLWLRQ,/LVDOVRDSRZHUIXOOF\WRNLQHZLWKDSUR LQÀDPPDWRU\DFWLYLW\,/ELQGV,/5DQGLQKLELWVWKHSURLQÀDPPDWRU\DFWLYLW\RI,/WKXV SHUIRUPLQJ D WKHUDSHXWLF DFWLRQ +HUH LQ WKLV DUWLFOH ZH UHYLHZ WKH UROH RI 0&V LQ UHODWLRQ WR SUR LQÀDPPDWRU\DQGDQWLLQÀDPPDWRU\,/IDPLO\PHPEHUF\WRNLQHVDQGDSRVVLEOHWKHUDSHXWLFHIIHFWLQ LQÀDPPDWRU\GLVRUGHUV Mast cells (MCs) are ubiquitous responses, EXW FDQ DOVR PHGLDWH LQÀDPPDWLRQ DIWHU immune cells that derive from hematopoietic stem activation by various molecules through the Toll- cells (CD34 +) and reside in all the vascularized like receptors, interleukin (IL)-1 receptors, and tissues and serous cavities where they reach the neurotransmitter receptors, without the intervention maturity (1). of IgE. Therefore, the binding of the antigen to these MCs are immune cells with a potential source of a receptors can activate MCs without degranulation (3). number of /, and growth factors Fc İRI receptor expressed on the cell surface of the that mediate allergic disease and participate in both 0&VELQGVWKHKLJKDI¿QLW\DQWLJHQDQGVWLPXODWHV LQQDWH DQG DGDSWLYH LPPXQH UHVSRQVHV   7KH\ the MCs with the initiation of phosphorylation. Fc İRI are effector cells that participate in IgE-mediated UHFHSWRULVPDGHXSRIDOSKDVXEXQLWVEHWDDQG

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Corresponding Author: Prof. Pio Conti, 0393-974X (2019) Copyright © by BIOLIFE, s.a.s. Postgraduate Medical School, University of Chieti, This publication and/or article is for individual use only and may not be further 9LDOH8QLWjG¶,WDOLD&KLHWL,WDO\ reproduced without written permission from the copyright holder. 8QDXWKRUL]HGUHSURGXFWLRQPD\UHVXOWLQ¿QDQFLDODQGRWKHUSHQDOWLHV 7HO)D[ 1 DISCLOSURE: ALL AUTHORS REPORT NO CONFLICTS OF e-mail: [email protected] INTEREST RELEVANT TO THIS ARTICLE.  C.E. GALLENGA ET AL.

WZRJDPPDXQLWVZKLFKVWDUWWKHUHDFWLRQDPSOL¿HG In this article, we discuss how MCs can be an by the 4 beta sub-units (1). Phosphorylation begins LPSRUWDQWVRXUFHRISURLQÀDPPDWRU\F\WRNLQHVWKDW with activation of and recruitment of PD\ EH LQKLELWHG E\ ,/ D PHPEHU RI WKH ,/ WKH&ȖSKRVSKROLSDVH 3/&Ȗ DQGSURWHLQNLQDVH& family (5) (Fig. 1.). (PKC) (1). In this pathway, intracellular calcium (Ca  ) is IL-1 regulated by PLC Ȗ  and PKC results in the formation IL-1 is one of the most important regulators of IP3 and diacylglycerol (DAG). MAPK, ERK, JNK of innate immune responses and participates in DQGSSDUWLFLSDWHLQWKHWUDQVFULSWLRQRIF\WRNLQHV QXPHURXVLQÀDPPDWRU\SURFHVVHV   and subsequently the generation of . It has been reported that MCs also contribute $FWLYDWLRQRIWKHSKRVSKROLSDVH$ 3/$ OHDGVWR to innate immunity and generate IL-1 upon the formation of prostaglandins (PGs), leukotrienes stimulation with LPS, bacteria and parasites. IL-1 (LTs) and lipoxins (LXs). All of these molecules, and JHQHUDWHGE\0&VSDUWLFLSDWHVLQWKHLQÀDPPDWRU\ others, including cytokines of the IL-1 family, are process in many disorders including autoimmune LQWHQVHO\LQYROYHGLQWKHLQÀDPPDWRU\SURFHVV   diseases, , atherosclerosis, , Members of the IL-1 family cytokines: IL-1, HQGRFULQRSDWKLHV DQG QHXURSDWKLHV   0& ,/ ,/ DQG ,/ SOD\ DQ LPSRUWDQW UROH LQ derived proteases are also able to activate IL-1, LPPXQHUHVSRQVHDQGLQÀDPPDWLRQ&\WRNLQHVVXFK in fact, serine protease chymase has been shown as TNF and IL-1 are produced by MCs and also have to convert pro-IL-1 ` into a biologically active the ability to activate MCs (4). form. Therefore, MC-derived proteases might act

)LJ 0DVWFHOODQWLJHQPHGLDWHGVLJQDOHYHQWVOHDGLQJWRGHJUDQXODWLRQDQGSURGXFWLRQRILQÀDPPDWRU\F\WRNLQHV Journal of Biological Regulators & Homeostatic Agents 3 secondary to caspase-1 activation and pro-IL-1 ` plays an indirect role on -mediated formation (9). immunity; while its direct participation is in , IL-1 is strongly involved in innate immunity, and pain, vasodilatation, hypotension, and in all those the cytoplasmic domain of the IL-1 receptor type GLVHDVHVZKHUHWKHUHLVLQÀDPPDWLRQ . IL-1 ` is also I, which binds IL-1, is similar to the cytoplasmic involved in the generation of adhesion molecules GRPDLQVRIDOO7ROOOLNHUHFHSWRUV 7/5V ,/ȕLV DQG FKHPRNLQHV ZLWK LQ¿OWUDWLRQ RI LQÀDPPDWRU\ a defense produced by the body, especially immune cells. It also plays a role in cancer and against infections, and is the most studied member metastasis, promoting and stem cell of the IL-1 family. The IL-1 family is made up of GLIIHUHQWLDWLRQRIP\HORLGFHOOVLQFOXGLQJ0&V    PHPEHUV LQFOXGLQJ ,/ ZKLFK ELQGV WKH 67 ,/ȕSDUWLFLSDWHVLQWKHSURGXFWLRQRI,/DQRWKHU receptor and performs various functions on the MCs. LPSRUWDQWSURLQÀDPPDWRU\F\WRNLQHDQGLQPDQ\ IL-1Ra binds to the IL-1RI receptor and inhibits cases, by blocking IL-1 `, IL-6 is also inhibited. IL-1 Į and IL-1 ` SHUIRUPLQJ DQWLLQÀDPPDWRU\ IL-1, together with a mitogen, participates in the activity. In the generation of IL-1, caspase-1 causes stimulation DQGDPSOL¿FDWLRQ of T cells, and acts on cleavage of the IL-1 ` precursor with formation WK\PRF\WHVDVDJURZWKIDFWRUFRQWULEXWLQJWR7+ and secretion of mature IL-1 `, a process that can cell polarization. Also in the formation of EHLQKLELWHGE\,/5DDQG,/,QLQÀDPPDWRU\ by plasma cells, IL-1 ` plays an important role and disease, by inhibiting IL-1 ` there is a reduction is a for B cells, probably through the LQ WKH V\PSWRPV DQG WKH LQÀDPPDWRU\ PROHFXOHV production of IL-6. It has been previously reported involved in the disease. In addition, IL-1 also that members of the IL-1 family are: IL-1 _, IL-1 `,

)LJ  Activated releases IL-1 family members including IL-37 which inhibits IL-1, and therefore LQÀDPPDWLRQ,QDGGLWLRQ,/UHOHDVHGE\PDVWFHOOLQGXFLQJLQÀDPPDWLRQLVDOVRLQKLELWHGE\,/ 4 C.E. GALLENGA ET AL.

,/5D,/,/,/ _, IL-36 `, IL-36 Ȗ, IL- ,/FDQH[SDQG7UHJFHOOV   5D ,/ ,/   %ORFNLQJ ,/ HJ ZLWK ,QKLELWLRQRILQÀDPPDWLRQDQGLPPXQHUHVSRQVH ,/RU,/5D RUGH¿FLHQW,/DQLPDOVVKRZD RFFXUV ZKHQ ,/ ELQGV WR WKH ,/5 _ ligand UHGXFWLRQLQWKHVHYHULW\RILQÀDPPDWRU\GLVHDVHDQG UHFHSWRUE\EORFNLQJWKHHQWLUHFDVFDGHLQ)LJ an increased vulnerability to infection. ,/FRPSULVHVYDULDQWVDEFGDQGHDQG may be induced in different tissues and cells, mainly IL-33 in peripheral blood mononuclear cells. Similarly IL-33 (also known as IL-1F11), which is an to IL-1, this cytokine, requires the cleavage of intracellular cytokine linked to the nucleus, controls FDVSDVHWREHDFWLYDWHG   LQÀDPPDWLRQ DQG LV LQYROYHG LQ WKH 7 KHOSHU  ,/ ELQGV WR WKH FHOO QXFOHXV DQG DFWV DV D 7K UHVSRQVHV  67UHFHSWRURI,/LV WUDQVFULSWLRQLVW FDUU\LQJ RXW DQ DQWLLQÀDPPDWRU\ composed of three extracellular Ig domains and an and immunosuppressive effects. intracellular Toll domain, and is similar to IL-1RI As IL-1 stimulates MCs and is produced by DQG ,/5Į UHFHSWRUV ,/ ELQGV 67 UHFHSWRU 0&VSHUIRUPLQJDQLPSRUWDQWLQÀDPPDWRU\DFWLRQ membrane and interacts with IL-1RAcP complex blocking IL-1 may exercise a new therapeutic DQG LQGXFHV 0\' IRU VLJQDO WUDQVGXFWLRQ 7KH DSSURDFK LQ LQÀDPPDWRU\ GLVHDVHV DQG WKHUHIRUH VWUXFWXUH RI ,/ LV PRUH VLPLODU WR ,/ WKDQ VKRXOGEHWDNHQLQWRFRQVLGHUDWLRQ   to IL1 ` and it induces the production of IL-6, IL- ȕDQG3*(IURP0&V,/SOD\VDFUXFLDOUROH IL-36 LQ SRO\QRPLDO GLVHDVHV E\ FDXVLQJ LQ¿OWUDWLRQ RI There are 3 subfamilies of IL-36 cytokine which and MCs (14). IL-33 induces IL-5 comprise IL-36 _,` a and one receptor antagonist IL- and IL-13 production, initiates NF- țB-mediated 5D  . IL-36 plays an important role in psoriasis signal transduction and causes changes in clinical where MCs play a crucial role. In fact, transgenic parameters in experimental animals. IL-1 induces IL- ,/ DQLPDOV VKRZ D VHYHUH LQÀDPPDWRU\ VNLQ 33 in MCs, and blocking IL-1 results in a noticeable pathology. IL-36 is therefore expressed mainly in the LPSURYHPHQWLQLQÀDPPDWRU\UHVSRQVH VNLQDQGDFWVRQ¿EUREODVWVDQGNHUDWLQRF\WHV7KLV cytokine is part of the IL-1 family and the maturation IL-37 of IL-36 is unclear. The proteins of the IL-1 family are important :KHQ ,/ ELQGV WR ,/ UHFHSWRU ,/5  for the defense of the host against external insults, the biological activity of IL-36 is inhibited. IL-36 is such as bacteria, parasites, fungi and , but also expressed in various organs, such as bone marrow and against tumor and autoimmune diseases. Several IL-1 , and in cells including CD4 + and IDPLO\F\WRNLQHVDUHSURLQÀDPPDWRU\EXWVRPHDUH dendritic cells. IL-36 is involved in the production DQWLLQÀDPPDWRU\DQGWDNHSDUWLQWKHUHJXODWLRQRI RI SURLQÀDPPDWRU\ F\WRNLQHV DQG SURPRWHV WKH LQÀDPPDWRU\EDODQFH polarization of T lymphocytes. $QWLLQÀDPPDWRU\ F\WRNLQHV LQ WKH ,/ IDPLO\ 0&VUHOHDVHYDULRXVSURLQÀDPPDWRU\FLWRNLQHV LQFOXGH,/DQG,/SURWHLQVDQGWZRUHFHSWRU including IL-36, which can take part in allergic antagonists, IL-1Ra and IL-36Ra (15). LQÀDPPDWLRQ ,QKLELWLQJ ,/ ZLWK ,/ FRXOG ,/ LV D F\WRNLQH PHPEHU RI WKH ,/ IDPLO\ be one of the solutions to alleviate the allergic ZLWK LPPXQRVXSSUHVVLYH DQG DQWLLQÀDPPDWRU\ LQÀDPPDWRU\SKHQRPHQRQ SURSHUWLHV,/LQGHHGSOD\VDFUXFLDOUROHLQWKH UHJXODWLRQRILQÀDPPDWRU\UHVSRQVHE\ORZHULQJWKH IL-38 OHYHOVRISURLQÀDPPDWRU\F\WRNLQHVUHODWHGWR,/ :KHQ ,/ ZDV ¿UVW GLVFRYHUHG LW ZDV ,/ DFWV DV DQ LQKLELWRU RI LQÀDPPDWLRQ DQG uncertain whether it was an agonist or an LQÀXHQFHVWKHDFWLRQRI7UHJFHOOVE\VXSSUHVVLQJWKH DQWDJRQLVWRILQÀDPPDWLRQ  7RGD\ZHNQRZ lymphocyte response. However, it is not clear how WKDW ,/ ELQGV WR WKH ,/5 UHFHSWRU DQG Journal of Biological Regulators & Homeostatic Agents 5

LQKLELWV,/SURLQÀDPPDWRU\DFWLRQDOWKRXJK FHOOV UHFHQW DGYDQFHV $QQX 5HY ,PPXQRO  LQVRPHFDVHV,/PDQLIHVWVLWVHOIDVDQDJRQLVW 5HYLHZ RIWKHLQÀDPPDWRU\SURFHVV7KHUHDVRQIRUWKLV  Conti P, Lessiani G, Kritas SK, Ronconi G, Caraffa GXDODFWLYLW\RI,/LVQRW\HWNQRZQ A, Theoharides TC. Mast cells emerge as mediators ,QDGGLWLRQ,/LVKRPRORJRXVWR,/5DDQG RI DWKHURVFOHURVLV 6SHFLDO HPSKDVLV RQ ,/ IL-1Ra, suggesting a similar antagonist function of LQKLELWLRQ7LVVXH&HOO   LQÀDPPDWLRQ 0RUHRYHU ,/ LV SDUW RI WKH ,/ 3. Taracanova A, Tsilioni I, Conti P, Norwitz ER, family and belongs to the IL-36 cytokine group. IL- Leeman SE, Theoharides TC. Substance P and LVH[SUHVVHGLQPDQ\WLVVXHVLQFOXGLQJVNLQVSOHHQ IL-33 administered together stimulate a marked tonsil, thymus, heart, fetal liver and placenta. VHFUHWLRQRI,/ȕIURPKXPDQPDVWFHOOVLQKLELWHG Some proteases, but not caspase-1, have been E\PHWKR[\OXWHROLQ3URF1DWO$FDG6FL86$ seen to split the cytokine IL-36; while proteases that   (( VSOLW,/5DDQG,/DUHXQNQRZQ ,/DFWVRQ 4. Conti P, D’Ovidio C, Conti C, et al. Progression in the IL-36R receptor, similar to IL-36Ra, inhibiting PLJUDLQH 5ROH RI PDVW FHOOV DQG SURLQÀDPPDWRU\ the biological effects of IL-36. To date it seems that DQG DQWLLQÀDPPDWRU\ F\WRNLQHV (XU - 3KDUPDFRO ,/ SHUIRUPV PDLQO\ DQWLLQÀDPPDWRU\ DFWLYLW\  by inhibiting IL-36. In some fungal infections, it 5. Conti P, Carinci F, Caraffa A, et al. Link between mast VHHPVWKDW,/LVYHU\LPSRUWDQWLQLQÀDPPDWRU\ cells and bacteria: Antimicrobial defense, function balance. 7KH LQKLELWRU\ HIIHFW RI ,/ PD\ SOD\ D DQGUHJXODWLRQE\F\WRNLQHV0HG+\SRWKHVHV role in rheumatic diseases where MCs play a crucial  role. +LJKOHYHOVRI,/DUHRIWHQDVVRFLDWHGZLWK 6. 'LQDUHOOR &$ ,PPXQRORJLFDO DQG LQÀDPPDWRU\ C-reactive (CRP) levels, and it could be a functions of the interleukin-1 family. Annu Rev PDUNHU RI LQÀDPPDWLRQ 7KH VXSSUHVVLRQ RI ,/ ,PPXQRO in in vitro leads to an increase in some  Tettamanti L, Kritas SK, Gallenga CE, et al. IL- SURLQÀDPPDWRU\ F\WRNLQHV VXFK DV ,/ ZKLFK LV 33 mediates through activation: also produced by activated MCs. The processed and Potential inhibitory effect of certain cytokines. J Biol WUXQFDWHG,/KDVDJUHDWLQKLELWRU\DFWLRQRQ,/ 5HJXO+RPHRVW$JHQWV   while the whole form can have a non-effect or even  Conti P, Caraffa A, Mastrangelo F, et al. Critical a stimulatory effect. This allows us to understand the UROHRILQÀDPPDWRU\PDVWFHOOLQ¿EURVLV3RWHQWLDO LPSRUWDQFHRI,/SURFHVVLQJ WKHUDSHXWLF HIIHFW RI ,/ &HOO 3UROLI  ,Q DGGLWLRQ ,/ LQKLELWV ,/ ,/ DQG ,/   H  ZKLFK SOD\ DQ LPSRUWDQW  UROH LQ VNLQ GLVHDVHV 9. Conti P, Caraffa A, Ronconi G, et al. Mast cells including psoriasis, a disease in which MCs give a clear SDUWLFLSDWH LQ DOORJUDIW UHMHFWLRQ FDQ ,/ SOD\ DQ FRQWULEXWLRQWRWKHLQÀDPPDWRU\SURFHVV7KHUHIRUH LQKLELWRU\UROH",QÀDPP5HV   RYHUH[SUHVVLRQRI,/OHDGVWRWKHLQKLELWLRQRI,/  Conti P, Tettamanti L, Mastrangelo F, et al. Impact DQGVRPHUHODWHGLQÀDPPDWRU\GLVHDVHV RI IXQJL RQ LPPXQH UHVSRQVHV &OLQ 7KHU  7KH VWXG\ RI SURLQÀDPPDWRU\ DQG DQWL    LQÀDPPDWRU\F\WRNLQHVDOORZVXVWREHWWHUXQGHUVWDQG 11. &DYDOOL*'LQDUHOOR&$6XSSUHVVLRQRILQÀDPPDWLRQ WKHQHWZRUNRILQÀDPPDWLRQWKDWLVIRXQGLQDOPRVW DQGDFTXLUHGLPPXQLW\E\,/,PPXQRO5HY all diseases, helping us to achieve new and effective    therapeutic compounds.  Cayrol C, Girard JP. Interleukin-33 (IL-33): A nuclear F\WRNLQHIURPWKH,/IDPLO\,PPXQRO5HY REFERENCES    13. Garlanda C, Dinarello CA, Mantovani A. The 1. Galli SJ, Kalesnikoff J, Grimbaldeston MA, et al. Mast interleukin-1 family: back to the future. Immunity cells as “tunable” effector and immunoregulatory    6 C.E. GALLENGA ET AL.

14. Caraffa A, Conti C, D Ovidio C, et al. New concepts 19. Luo Y, Cai X, Liu S, et al. Suppression of antigen- LQ QHXURLQÀDPPDWLRQ PDVW FHOOV SURLQÀDPPDWRU\ VSHFL¿FDGDSWLYHLPPXQLW\E\,/YLDLQGXFWLRQRI DQG DQWLLQÀDPPDWRU\ F\WRNLQH PHGLDWRUV - %LRO tolerogenic dendritic cells. Proc Natl Acad Sci U S A 5HJXO+RPHRVW$JHQWV      15. Conti P, Ronconi G, Kritas SK, Caraffa A, Theoharides  Varvara G, Tettamanti L, Gallenga CE, Caraffa TC. Activated mast cells mediate low-grade A, D’Ovidio C, Mastrangelo F, Ronconi G, LQÀDPPDWLRQLQ7\SH'LDEHWHV,QWHUOHXNLQ&RXOG Kritas SK, Conti P. Stimulated mast cells release %H%HQH¿FLDO&DQ-'LDEHWHV   LQÀDPPDWRU\ F\WRNLQHV SRWHQWLDO VXSSUHVVLRQ DQG 16. Coll-Miró M, Francos-Quijorna I, Santos-Nogueira therapeutical aspects. J Biol Regul Homeost Agents (HWDO%HQH¿FLDOHIIHFWVRI,/DIWHUVSLQDOFRUG    LQMXU\ LQ PLFH 3URF 1DWO $FDG 6FL 8 6 $   van de Veerdonk FL, Stoeckman AK, Wu G, 113(5):1411-16. Boeckermann AN, Azam T, Netea MG, Joosten LA,  Conti P, Caraffa A, Ronconi G, et al. Impact of mast van der Meer JW, Hao R, Kalabokis V, Dinarello CA. FHOOVLQPXFRVDOLPPXQLW\RILQWHVWLQDOLQÀDPPDWLRQ ,/ELQGVWRWKH,/UHFHSWRUDQGKDVELRORJLFDO ,QKLELWRU\ HIIHFW RI ,/ (XU - 3KDUPDFRO  effects on immune cells similar to IL-36 receptor  DQWDJRQLVW 3URF 1DWO $FDG 6FL 8 6 $   Conti P, Carinci F, Lessiani G, et al. Potential    WKHUDSHXWLFXVHRI,/DNH\VXSSUHVVRURILQQDWH  van de Veerdonk FL, de Graaf DM, Joosten immunity and allergic immune responses mediated /$'LQDUHOOR&$%LRORJ\RI,/DQGLWVUROHLQ E\PDVWFHOOV,PPXQRO5HV   GLVHDVH,PPXQRO5HY