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Say it isn’t pso: IL-25 drives skin inflammation

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Science Immunology  04 May 2018:
Vol. 3, Issue 23, eaat9662
DOI: 10.1126/sciimmunol.aat9662

Abstract

IL-25 from keratinocytes mediates skin inflammation in psoriasis.

Psoriasis is a common chronic inflammatory skin disease. Although much is known about the cellular molecular pathogenesis of this disease there is still plenty to be learned. Specifically, the role keratinocytes play in establishing and maintaining disease pathology remains to be elucidated. Several studies have demonstrated a role for the interleukin 17 (IL-17) family of cytokines in the pathogenesis of psoriasis. One IL-17 family member, interleukin 25 (IL-25 or IL-17E), has been shown to be involved in several inflammatory diseases, but its role in psoriasis is poorly understood.

In this recent study, Xu et al. dissected the role of IL-25 in the initiation and maintenance of psoriasis. The authors show that IL-25 is expressed in skin lesions of psoriasis patients. IL-25 expression was also observed in the skin lesions of a mouse model of psoriasis in which topical application of the Toll-like receptor 7 (TLR7)–agonist imiquimod induces a condition that recapitulates many aspects of the human disease. Interestingly, intradermal administration of recombinant IL-25 was sufficient to drive psoriasis-like disease in mice. Expression of this cytokine is regulated by IL-17A, because IL-17A knockout mice have lower IL-25 expression in the imiquimod model. Imiquimod-induced disease was also substantially diminished in global IL-25 knockout mice. Keratinocyte-derived IL-25 was essential for driving the imiquimod induced-disease; pathology was notably attenuated in mice with keratinocyte-selective deletion of the IL-25 gene. During disease, keratinocytes also expressed the IL-25 receptor, interleukin 17 receptor B (IL-17RB). An IL-17RB–IL-25 feedback loop drove keratinocyte proliferation and inflammatory gene expression in a STAT3-dependent manner, and treating with anti–IL-25 ameliorated disease. Although IL-17 cytokines are important to mount productive immune responses against pathogens, IL-25 from keratinocytes was dispensable in clearing cutaneous infection with Staphylococcus aureus. Taken together, these data suggest that IL-17A expression during the initiation of psoriasis drives the expression of IL-25 from keratinocytes and this cytokine then regulates the proliferation of keratinocytes to maintain psoriasiform inflammation in an autocrine manner. If these findings are validated in humans, inhibition of IL-25 may prove to be a novel therapeutic target in the treatment of psoriasis and associated diseases.

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