Advances in Mast Cell Activation by IL-1 and IL-33 in Sjögren’s Syndrome: Promising Inhibitory Effect of IL-37

Pio Conti,Ilias Frydas,Ali Younes,Spyros K. Kritas,Alesssandro Caraffa,Carla E. Gallenga,Rhiannon Ross,Paolo Di Emidio,Luisa Stellin,Gianpaolo Ronconi

doi:10.3390/ijms21124297

Abstract

Sjögren’s syndrome (SS) is a chronic autoimmune inflammatory disease that affects primarily older women and is characterized by irreversible damage of the exocrine glands, including tear (xerophthalmia) and salivary glands (xerostomia). Secretory glands lose their functionality due to the infiltration of immune cells, which produce cytokines and cause inflammation. Primary SS is characterized by dry syndrome with or without systemic commitment in the absence of other pathologies. Secondary SS is accompanied by other autoimmune diseases with high activation of B lymphocytes and the production of autoantibodies, including the rheumatoid factor. Other cells, such as CD4+ T cells and mast cells (MCs), participate in SS inflammation. MCs are ubiquitous, but are primarily located close to blood vessels and nerves and can be activated early in autoimmune diseases to express a wide variety of cytokines and chemokines. In the SS acute phase, MCs react by generating chemical mediators of inflammation, tumor necrosis factor (TNF), and other pro-inflammatory cytokines such as interleukin (IL)-1 and IL-33. IL-33 is the specific ligand for ST2 capable of inducing some adaptive immunity TH2 cytokines but also has pro-inflammatory properties. IL-33 causes impressive pathological changes and inflammatory cell infiltration. IL-1 family members can have paracrine and autocrine effects by exacerbating autoimmune inflammation. IL-37 is an IL-1 family cytokine that binds IL-18Rα receptor and/or Toll-like Receptor (TLR)4, exerting an anti-inflammatory action. IL-37 is a natural inhibitor of innate and acquired immunity, and the level is abnormal in patients with autoimmune disorders. After TLR ligand activation, IL-37 mRNA is generated in the cytoplasm, with the production of pro-IL-37 and later mature IL-37 caspase-1 mediated; both precursor and mature IL-37 are biologically active. Here, we discuss, for the first time, the current knowledge of IL-37 in autoimmune disease SS and propose a new therapeutic role.

Highlights

The first description of autoimmune diseases occurred in the late 19th century
In the more common secondary s syndrome (SS) form, associated with other rheumatic autoimmune diseases, there is an infiltration of immune cells in various organs, such as endocrine glands, and deposition of various autoantibodies including rheumatoid factor (RF), anti-Ro60/SS-A and anti-La/SS-B, which provoke inflammation mediated by pro-inflammatory cytokines [9]
In the acute phase of Primary Sjögren’s syndrome (pSS), where low-grade systemic inflammation can occur, there is an over-expression of several pro-inflammatory cytokines, such as tumor necrosis factor (TNF) and IL-1 family members generated by immune cells including mast cells (MCs) [35]

Summary

Introduction

The first description of autoimmune diseases occurred in the late 19th century. Today, there are over 80 autoimmune disorders, where it is noted that the immune system attacks its cells or tissues, causing functional damage to the organs [1]. In the more common secondary SS form, associated with other rheumatic autoimmune diseases, there is an infiltration of immune cells in various organs, such as endocrine glands, and deposition of various autoantibodies including rheumatoid factor (RF), anti-Ro60/SS-A and anti-La/SS-B, which provoke inflammation mediated by pro-inflammatory cytokines [9]. 2020, 21, 4297 regulating the function of IL-33 produced by MCs could be crucial in the treatment of autoimmune inflammatory diseases mediated by this important cytokine [32].

Results

Conclusion