Abstract
Psoriasis (PS) is a skin disease with autoimmune features mediated by immune cells, which typically presents inflammatory erythematous plaques, and is associated with many comorbidities. PS exhibits excessive keratinocyte proliferation, and a high number of immune cells, including macrophages, neutrophils, Th1 and Th17 lymphocytes, and mast cells (MCs). MCs are of hematopoietic origin, derived from bone marrow cells, which migrate, mature, and reside in vascularized tissues. They can be activated by antigen-provoking overexpression of proinflammatory cytokines, and release a number of mediators including interleukin (IL)-1 and IL-33. IL-1, released by activated keratinocytes and MCs, stimulates skin macrophages to release IL-36—a powerful proinflammatory IL-1 family member. IL-36 mediates both innate and adaptive immunity, including chronic proinflammatory diseases such as psoriasis. Suppression of IL-36 could result in a dramatic improvement in the treatment of psoriasis. IL-36 is inhibited by IL-36Ra, which binds to IL-36 receptor ligands, but suppression can also occur by binding IL-38 to the IL-36 receptor (IL-36R). IL-38 specifically binds only to IL-36R, and inhibits human mononuclear cells stimulated with IL-36 in vitro, sharing the effect with IL-36Ra. Here, we report that inflammation in psoriasis is mediated by IL-1 generated by MCs—a process that activates macrophages to secrete proinflammatory IL-36 inhibited by IL-38. IL-37 belongs to the IL-1 family, and broadly suppresses innate inflammation via IL-1 inhibition. IL-37, in murine models of inflammatory arthritis, causes the suppression of joint inflammation through the inhibition of IL-1. Therefore, it is pertinent to think that IL-37 can play an inhibitory role in inflammatory psoriasis. In this article, we confirm that IL-38 and IL-37 cytokines emerge as inhibitors of inflammation in psoriasis, and hold promise as an innovative therapeutic tool.
Highlights
Introduction conditions of the Creative CommonsApproximately 3% of the population of the United States of America and 2% of the global population suffer from psoriasis
This article focused on the contribution of mast cells (MCs) and their secreted and released products to psoriatic inflammation, demonstrating that these cells are very important in aggravating the disease—a process that can be limited with the use of new anti-inflammatory cytokines such as IL-37, IL-38, or IL-1 receptor antagonist (IL-1Ra)
By binding to the IL-36 receptor, IL-38 inhibits human mononuclear cells stimulated with IL-36 in vitro—an effect shared with IL-36 receptor antagonist (IL-36Ra), which it resembles for its inhibitory effects, in particular on the Th-17 response [70]
Summary
3% of the population of the United States of America and 2% of the global population suffer from psoriasis. Psoriasis is a disease believed to be of autoimmune nature, which causes scaly patches on the skin and redness in the lesions, due to the increased numbers of capillaries. Cytokines produced by activated immune cells contribute to the induction of psoriasis [6]. Dendritic cells—key sentinels of the immune system—are increased in psoriatic lesions, and favor the production of Th1 cells and secretion of proinflammatory cytokines and nitric oxide [12]. Macrophages, and MCs are activated through Toll-like receptors (TLRs), leading to cytokine/chemokine production and induction of inflammation [13]. The cytokines IL-1, tumor necrosis factor (TNF), and IL-6 are secreted at the site of the lesion by keratinocytes These cytokines activate dendritic cells which, in turn, produce cytokines. Sci. 2021, 22, x FOR PEER REVIEW likely that blocking one of these steps above may result in a relief of psoriasis [15]
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