IL-1RL2 and Its Ligands Contribute to the Cytokine Network in Psoriasis

Abstract

Psoriasis is a common immune-mediated disease in European populations; it is characterized by inflammation and altered epidermal differentiation leading to redness and scaling. T cells are thought to be the main driver, but there is also evidence for an epidermal contribution. In this article, we show that treatment of mouse skin overexpressing the IL-1 family member, IL-1F6, with phorbol ester leads to an inflammatory condition with macroscopic and histological similarities to human psoriasis. Inflammatory cytokines thought to be important in psoriasis, such as TNF-α, IL-17A, and IL-23, are upregulated in the mouse skin. These cytokines are induced by and can induce IL-1F6 and related IL-1 family cytokines. Inhibition of TNF or IL-23 inhibits the increased epidermal thickness, inflammation, and cytokine production. Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice. These data suggest a role for IL-1F family members in psoriasis.

Psoriasiform dermatitis is driven by IL-36–mediated DC-keratinocyte crosstalk

“…These results suggest that IL-36 contributes to a small but not negligible degree to lesion development beyond induction of IL-23/IL-17/IL-22 axis in the IMQ psoriasis model. Notably, 12-O-tetradecanoylphorbol-13-acetate treatment of K14-IL-36α transgenic mice induced psoriasiform dermatitis also on a lymphocyte-deficient rag2 −/− background, indicating that T cells and their pathological mediators, IL-17 and IL-22, are completely dispensable in this transgenic mouse model (32).…”

“…Current evidence implicating IL-36 cytokines in the development of psoriasis is mainly based on transgenic mice that develop dermatitis due to forced overexpression of IL-36α in the epidermis (31,32) and the recent identification of IL-36R antagonist loss-offunction mutations in patients with a rare and very severe form of psoriasis termed generalized pustular psoriasis (33,34). To our knowledge, our study demonstrates for the first time that IL-36R signaling is absolutely crucial for control of the pathogenic IL-23/IL-17/IL-22 axis and development of psoriasiform dermatitis in response to environmental cues triggering TLR7 on skin DCs (i.e., using topical application of IMQ).…”

“…Increased levels of IL-36 cytokines and IL-36R were observed in lesions of human psoriatic skin and confirmed in mouse models of psoriasis-like diseases (28)(29)(30). IL-36α overexpression in keratinocytes of K14-IL-36α transgenic mice was reported to result in a transient inflammatory skin disorder at birth that waned after 2 to 3 weeks of age (31) but rendered mice highly susceptible to 12-O-tetrade-canoylphorbol-13-acetate and induced skin pathology reminiscent of human psoriasis (32). Moreover, removal of the IL36RN gene in K14-IL-36α transgenic mice induced chronic and aggravated skin abnormalities, and mutations in IL36RN were recently described in patients with pustular psoriasis (33,34).…”

IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells

“…4,[11][12][13] IL-36 plays a major role in mouse experimental skin inflammation and in human psoriasis both in the initiation and regulation of inflammatory responses. [14][15][16][17][18][19] Furthermore, the association of a form of generalized pustular psoriasis with genetic IL-36Ra deficiency in humans argues in favor of a significant role of IL-36 in inflammatory skin diseases. 20,21 Recently, we have shown that dendritic cells (DCs) express IL-36R and that IL-36 stimulates the production of several cytokines and enhances the expression of costimulatory molecules in bone marrow-derived DCs (BMDCs).…”

The Role of Cytokines of Interleukin 36 Family in Immunopathogenesis of Psoriasis

“…Введение иммунодефицитным мышам, кото-рым был пересажен участок пораженной кожи больного псориазом, IL-36R-нейтрализующих моноклональных антител приводило к клиниче-скому улучшению и существенному уменьшению эпидермальной гиперплазии и других патомор-фологических изменений, характерных для псо-риаза [4].…”