Preview

Medical Immunology (Russia)

Advanced search

Pathogenetic role of IL-4 and IL-13 in atopic dermatitis: The inhibitory pathways

https://doi.org/10.15789/1563-0625-PRO-3070

Abstract

The review article is devoted to the two key Th2 cytokines, IL-4 and IL-13, which are directly involved in the immunopathogenesis of atopic dermatitis (AD). The identification of IL-4 and IL-13 in AD was first reported by Q. Hamid et al. in 1994. Since then, a number of studies have appeared confirming the relationship of these Th2 cytokines with disruption of the skin epidermal barrier; a decrease in skin immune response due to inhibited expression of antimicrobial peptides against Staphylococcus aureus, etc. The convincing studies also confirm a relationship with IL-4/IL-13 to such clinical manifestations of ADs as skin infections, as well as inflammation, lichenification and itching of the skin. The role of IL-4 and IL-13 is also confirmed by clinical studies, which indicate a beneficial effect of drugs inhibiting these cytokines on the relief of skin symptoms in atopic dermatitis (itching, rashes). The IL-4 and IL-13 are shown to connect the JAK/STAT signaling pathway due to the common α-subunit of IL-4 receptor (IL-4Rα). Importantly, IL-4, IL-13 and other cytokines (including IL-31) are capable of activating the sensory neurons, thus being often considered potent pruritogens. The article also discusses issues related to the role of the JAK/STAT signaling pathway and, in particular, the JAK1 protein in development of atopic dermatitis. As based on pathogenetic significance of IL-4 and IL-13, drugs have recently been developed that block their activity and, thereby, affect important molecular pathways of the AD development. These drugs are classified as systemic medications which include, e.g., (1) biological therapy (dupilumab, the first monoclonal IgG4 antibody), which blocks IL-4Rα and, thereby, suppresses the IL-4/IL-13 axis, and (2). Janus kinase (JAK) inhibitors or small-molecule agents. Currently, some Janus kinase inhibitors, e.g., abrocitinib, upadacitinib, and barocitinib, are available in Russia. Clinical studies show that both biological therapy and small molecules have an immunomodulatory effect on the course of atopic dermatitis. The review briefly presents the main data of recent meta-analyses on the comparative characteristics of biotherapy and usage of Janus kinase inhibitors in this disorder.

About the Author

D. Sh. Macharadze
G. Gabrichevsky Research Institute of Epidemiology and Microbiology
Russian Federation

Macharadze D.Sh., PhD, MD (Medicine), Leading Research Associate, Clinical Department 

10 Admiral Makarov St., Moscow, 125212



References

1. Alkon N., Bauer W.M., Krausgruber T., Goh I., Griss J., Nguyen V., Reininger B., Bangert C., Staud C., Brunner PM., Bock C., Haniffa M., Stingl G. Single-cell analysis reveals innate lymphoid cell lineage infidelity in atopic dermatitis. J. Allergy Clin. Immunol., 2022, Vol. 149, no. 2, pp. 624-639.

2. Ari Ariëns L., van der Schaft J., Bakker D.S., Balak D., Romeijn M.L.E., Kouwenhoven T., Kamsteeg M., Giovannone B., Drylewicz J., van Amerongen C.C.A., Delemarre E.M., Knol E.F., van Wijk F., Nierkens S., Thijs J.L., Schuttelaar M.L.A., de Bruin-Weller M.S. Dupilumab is very effective in a large cohort of difficult-to-treat adult atopic dermatitis patients: First clinical and biomarker results from the BioDay registry. Allergy, 2020, Vol. 75, no. 1, pp. 116-126.

3. Banerjee S., Biehl A., Gadina M., Hasni S., Schwartz D.M. JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs, 2017, Vol. 77, no. 5, pp. 521-546.

4. Baurecht H., Rühlemann M.C., Rodríguez E., Thielking F., Harder I., Erkens A.S., Stölzl D., Ellinghaus E., Hotze M., Lieb W., Wang S., Heinsen-Groth F.A., Franke A., Weidinger S. Epidermal lipid composition, barrier integrity, and eczematous inflammation are associated with skin microbiome configuration. J. Allergy Clin. Immunol., 2018, Vol. 141, no. 5, pp. 1668-1676.e16.

5. Bieber T. Atopic dermatitis. N. Engl. J. Med., 2008, Vol. 358, no. 14, pp. 1483-1494.

6. Bieber T. Interleukin-13: Targeting an underestimated cytokine in atopic dermatitis. Allergy, 2020, Vol. 75, no. 1, pp. 54-62.

7. Brandt E.B., Sivaprasad U. Th2 cytokines and atopic dermatitis. J. Clin. Cell Immunol., 2011, Vol. 2, no. 3, 110. doi: 10.4172/2155-9899.1000110.

8. Brightling C.E., Saha S., Hollins F. Interleukin-13: prospects for new treatments. Clin. Exp. Allergy, 2010, Vol. 40, no. 1, pp. 42-49.

9. Chan L.S., Robinson N., Xu L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J. Invest. Dermatol., 2001, Vol. 117, no. 4, pp. 977-983.

10. Chapman S., Kwa M., Gold L.S., Lim H.W. Janus kinase inhibitors in dermatology: Part I. A comprehensive review. J. Am. Acad. Dermatol., 2022, Vol. 86, no. 2, pp. 406-413.

11. Darlenski R., Kozyrskyj A.L., Fluhr J.W., Caraballo L. Association between barrier impairment and skin microbiota in atopic dermatitis from a global perspective: Unmet needs and open questions. J. Allergy Clin. Immunol., 2021, Vol. 148, no. 6, pp. 387-1393.

12. de Welsch K., Holstein J., Laurence A., Ghoreschi K. Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors. Effectiveness of dupilumab treatment in 95 patients with atopic dermatitis: daily practice data. Br. J. Dermatol., 2020, Vol. 182, no. 2, pp. 418-426.

13. Domínguez-Hüttinger E., Christodoulides P., Miyauchi K., Irvine A.D., Okada-Hatakeyama M., Kubo M., Tanaka R.J. Mathematical modeling of atopic dermatitis reveals “double-switch” mechanisms underlying 4 common disease phenotypes. J. Allergy Clin. Immunol., 2017, Vol. 139, no. 6, pp. 1861-1872.e7.

14. Dubin C., Del Duca E., Guttman-Yassky E. The IL-4, IL-13 and IL-31 pathways in atopic dermatitis. Expert Rev. Clin. Immunol. 2021, Vol. 17, pp. 835-852.

15. Facheris P., Jeffery J., Del Duca E., Guttman-Yassky E. The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment. Cell. Mol. Immunol., 2023, Vol. 20, no. 5, pp. 448-474.

16. Fukuyama T., Ganchingco J.R., Mishra S.K., Olivry T., Rzagalinski I., Volmer D.A., Bäumer W. Janus kinase inhibitors display broad anti-itch properties: A possible link through the TRPV1 receptor. J. Allergy Clin. Immunol., 2017, Vol. 140, no. 1, pp. 306-309.e3.

17. Furue M., Ulzii D., Vu Y.H., Tsuji G., Kido-Nakahara M., Nakahara T. Pathogenesis of atopic dermatitis: current paradigm. Iran J. Immunol., 2019, Vol. 16, no. 2, pp. 97-107.

18. Furue M. Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4-JAKSTAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis. J. Clin. Med., 2020, Vol. 9, no. 11, 3741. doi: 10.3390/jcm9113741.

19. Guttman-Yassky E., Irvine A.D., Brunner P.M., Kim B.S., Boguniewicz M., Parmentier J., Platt A.M., Kabashima K. The role of Janus kinase signaling in the pathology of atopic dermatitis. J. Allergy Clin. Immunol., 2023, Vol. 152, no. 6, pp. 1394-1404.

20. Hamid Q., Boguniewicz M., Leung D.Y. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J. Clin. Invest., 1994, Vol. 94, no. 2, pp. 870-876.

21. He H., Guttman-Yassky E. JAK inhibitors for atopic dermatitis: an update. Am. J. Clin. Dermatol., 2019, Vol. 20, no. 2, pp. 181-192.

22. Huang I.H., Chung W.H., Wu P.C., Chen C.B. JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review. Front. Immunol., 2022, Vol. 13,1068260. doi: 10.3389/fimmu.2022.1068260.

23. Ingrassia J.P., Maqsood M.H., Gelfand J.M., Weber B.N., Bangalore S., Lo Sicco K.I., Garshick M.S. Cardiovascular and venous thromboembolic risk with JAK inhibitors in immune-mediated inflammatory skin diseases: a systematic review and meta-analysis. JAMA Dermatol., 2024, Vol. 160, no. 1, pp. 28-36.

24. Izuhara K., Arima K., Yasunaga S. IL-4 and IL-13: their pathological roles in allergic diseases and their potential in developing new therapies. Curr. Drug Targets Inflamm. Allergy, 2002, Vol. 1, no. 3, pp. 263-269.

25. Kim B.S., Siracusa M.C., Saenz S.A., Noti M., Monticelli L.A., Sonnenberg G.F., Hepworth M.R., Van Voorhees A.S., Comeau M.R., Artis D. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci. Transl. Med., 2013, Vol. 5, no. 170, 170ra16. doi: 10.1126/scitranslmed.3005374.

26. Kim R.W., Lam M., Abuabara K., Simpson E.L., Drucker A.M. Targeted systemic therapies for adults with atopic dermatitis: selecting from biologics and JAK inhibitors. Am. J. Clin. Dermatol., 2024, Vol. 25, no. 2, pp. 179-193.

27. Lamiable O., Brewerton M., Ronchese F. IL-13 in dermal type-2 dendritic cell specialization: From function to therapeutic targeting. Eur. J. Immunol., 2022, Vol. 52, no. 7, pp. 1047-1057.

28. Leyva-Castillo J.M., Geha R.S. Cutaneous type 2 innate lymphoid cells come in distinct flavors. JID Innov., 2021, Vol. 1, no. 3, 100059. doi: 10.1016/j.xjidi.2021.100059.

29. Leung D.Y., Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J. Allergy Clin. Immunol., 2014, Vol. 134, no. 4, pp. 769-779.

30. Nakashima C., Yanagihara S., Otsuka A. Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors. Allergol. Int., 2022, Vol. 71, no. 1, pp. 40-46.

31. Oetjen L.K., Mack M.R., Feng J., Whelan T.M., Niu H., Guo C.J., Chen S., Trier A.M., Xu A.Z., Tripathi S.V., Luo J., Gao X., Yang L., Hamilton S.L., Wang P.L., Brestoff J.R., Council M.L., Brasington R., Schaffer A., Brombacher F., Hsieh C.S., Gereau R.W., Miller M.J., Chen Z.F., Hu H., Davidson S., Liu Q., Kim B.S. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell. 2017, Vol. 171, no. 1, pp. 217-228.e13.

32. Ong P.Y. Atopic dermatitis: is innate or adaptive immunity in control? A clinical perspective. Front. Immunol., 2022, Vol. 13, 943640. doi: 10.3389/fimmu.2022.943640.

33. Pavel P., Blunder S., Moosbrugger-Martinz V., Elias P.M., Dubrac S. Atopic dermatitis: the fate of the fat. Int. J. Mol. Sci., 2022, Vol. 23, no. 4, p. 2121. doi: 10.3390/ijms23042121.

34. Roesner L.M., Zeitvogel J., Heratizadeh A. Common and different roles of IL-4 and IL-13 in skin allergy and clinical implications. Curr. Opin. Allergy Clin. Immunol., 2019, Vol. 19, no. 4, pp. 319-327.

35. Rojahn T.B., Vorstandlechner V., Krausgruber T., Bauer W.M., Alkon N., Bangert C., Thaler F.M., Sadeghyar F., Fortelny N., Gernedl V., Rindler K., Elbe-Bürger A., Bock C., Mildner M., Brunner P.M. Single-cell transcriptomics combined with interstitial fluid proteomics defines cell type-specific immune regulation in atopic dermatitis. J. Allergy Clin. Immunol., 2020, Vol. 146, no. 5, pp. 1056-1069.

36. Sharma M., Leung D., Momenilandi M., Jones L.C.W., Pacillo L., James A.E., Murrell J.R., Delafontaine S., Maimaris J., Vaseghi-Shanjani M., Del Bel K.L., Lu H.Y., Chua G.T., Di Cesare S., Fornes O., Liu Z., Di Matteo G., Fu M.P., Amodio D., Tam I.Y.S., Chan G.S.W., Sharma A.A., Dalmann J., van der Lee R., Blanchard-Rohner G., Lin S., Philippot Q., Richmond P.A., Lee J.J., Matthews A., Seear M., Turvey A.K., Philips R.L., Brown-Whitehorn T.F., Gray C.J., Izumi K., Treat J.R., Wood K.H., Lack J., Khleborodova A., Niemela J.E., Yang X., Liang R., Kui L., Wong C.S.M., Poon G.W.K., Hoischen A., van der Made C.I., Yang J., Chan K.W., Rosa Duque J.S.D., Lee P.P.W., Ho M.H.K., Chung BHY, Le H.T.M., Yang W., Rohani P., Fouladvand A., Rokni-Zadeh H., Changi-Ashtiani M., Miryounesi M., Puel A., Shahrooei M., Finocchi A., Rossi P., Rivalta B., Cifaldi C., Novelli A., Passarelli C., Arasi S., Bullens D., Sauer K., Claeys T., Biggs C.M., Morris E.C., Rosenzweig S.D., O’Shea J.J., Wasserman W.W., Bedford H.M., van Karnebeek C.D.M., Palma P., Burns S.O., Meyts I., Casanova J.L., Lyons J.J., Parvaneh N., Nguyen A.T.V., Cancrini C., Heimall J., Ahmed H., McKinnon M.L., Lau Y.L., Béziat V., Turvey S.E. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease. J. Exp. Med., 2023, Vol. 220, 20221755. doi: 10.1084/jem.20221755.

37. Simpson E.L., Schlievert P.M., Yoshida T., Lussier S., Boguniewicz M., Hata T., Fuxench Z., de Benedetto A., Ong P.Y., Ko J., Calatroni A., Rudman Spergel A.K., Plaut M., Quataert S.A., Kilgore S.H., Peterson L., Gill A.L., David G., Mosmann T., Gill S.R., Leung D.Y.M., Beck L.A. Rapid reduction in Staphylococcus aureus in atopic dermatitis subjects following dupilumab treatment. J. Allergy Clin. Immunol., 2023, Vol. 152, no. 5, pp. 1179-1195.

38. Su Z., Zeng Y.P. Dupilumab-associated psoriasis and psoriasiform manifestations: a scoping review. Dermatology, 2023, Vol. 239, no. 4, pp. 646-657.

39. Sugaya M. The role of Th17-related cytokines in atopic dermatitis. Int. J. Mol. Sci., 2020, Vol. 21, no. 4, 1314. doi: 10.3390/ijms21041314.

40. Tatsuno K., Fujiyama T., Yamaguchi H., Waki M., Tokura Y. TSLP directly interacts with skin-homing Th2 cells highly expressing its receptor to enhance IL-4 Production in Atopic Dermatitis. J. Invest. Dermatol., 2015, Vol. 135, no. 12, pp. 3017-3024.

41. Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J. Dermatol. Sci., 2010, Vol. 58, no. 1, pp. 1-7.

42. Toyama S., Tominaga M., Takamori K. Connections between immune-derived mediators and sensory nerves for itch sensation. Int. J. Mol. Sci., 2021, Vol. 22, no. 22, 12365. doi: 10.3390/ijms222212365.

43. Tsoi L.C., Rodriguez E., Degenhardt F., Baurecht H., Wehkamp U., Volks N., Szymczak S., Swindell W.R., Sarkar M.K., Raja K., Shao S., Patrick M., Gao Y., Uppala R., Perez White B.E., Getsios S., Harms P.W., Maverakis E., Elder J.T., Franke A., Gudjonsson J.E., Weidinger S. Atopic dermatitis Is an IL-13-dominant disease with greater molecular heterogeneity compared to psoriasis. J. Invest. Dermatol., 2019, Vol. 139, no. 7, pp. 1480-1489.

44. Welsch K., Holstein J., Laurence A., Ghoreschi K. Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors. Eur. J. Immunol., 2017, Vol. 47, no. 7, pp. 1096-1107.

45. Xiao S., Lu Z., Steinhoff M., Li Y., Buhl T., Fischer M., Chen W., Cheng W., Zhu R., Yan X., Yang H., Liu Y., Dou Y., Wang W., Wang J., Meng J. Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis. Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis. Brain Behav. Immun., 2021, Vol. 98, pp. 28-39.

46. Zheng T., Oh M.H., Oh S.Y., Schroeder J.T., Glick A.B., Zhu Z. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J. Invest. Dermatol., 2009, Vol. 129, no. 3, pp. 742-451.


Supplementary files

Review

For citations:


Macharadze D.Sh. Pathogenetic role of IL-4 and IL-13 in atopic dermatitis: The inhibitory pathways. Medical Immunology (Russia). 2025;27(2):287-296. (In Russ.) https://doi.org/10.15789/1563-0625-PRO-3070

Views: 324


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 1563-0625 (Print)
ISSN 2313-741X (Online)