Mast Cell Cytokines IL-1, IL-33, and IL-36 Mediate Skin Inflammation in Psoriasis: A Novel Therapeutic Approach with the Anti-Inflammatory Cytokines IL-37, IL-38, and IL-1Ra

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.

Integration and Reanalysis of Four RNA-Seq Datasets Including BALF, Nasopharyngeal Swabs, Lung Biopsy, and Mouse Models Reveals Common Immune Features of COVID-19

“…trypase and chymase), arachidonic acid products (e.g. prostaglandins and leukotrienes), growth factors, and cytokines and chemokines, thereby participating in many types of innate and adaptive immune responses ( 73 ). Mast cells are an important source of proinflammatory cytokines including TNFα and IL-1β.…”

“…For instance, mast cell-derived IL-1 including IL1α and IL1β in synovial joint contributes to the initiation of autoimmune inflammation in autoantibody-mediated arthritis ( 74 ). The production of IL1 by mast cells could increases the number of infiltrating neutrophils with their release of proteases and rising inflammation ( 73 ). In addition, it has also been shown that stabilizing mast cells prevents apoptosis and sepsis ( 75 ), both of which exacerbate COVID-19 symptoms.…”

Unmet Medical Needs in Chronic, Non-communicable Inflammatory Skin Diseases

“…Other interesting developments also include mediators that have been primarily attributed to more innate immune mechanisms that may factor more strongly in therapeutic considerations and developments. A good example of this is the development of IL-36 antagonists or blockade of other members of the IL-1 family ( 83 ), which are proving to be promising in pustular and highly inflammatory forms of psoriasis ( 84 ). Besides biologics, small-molecules which are orally available and able to penetrate cells are being pursued.…”

Eosinophil count and tumor necrosis factor α in response to phototherapy treatment of neonatal hyperbilirubinemia: a cross sectional study

“…It was also found to have a strong association with allergic rhinitis and conjunctivitis [ 8 ] . This was explained by the PT 's ability to influence the synthesis and release of cytokines from the peripheral immune system as interleukin IL-1, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-alfa) [ 9 ] .…”