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

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.

Biomimetic Human Disease Model of SARS‐CoV‐2‐Induced Lung Injury and Immune Responses on Organ Chip System

“…Circulating cytokines, including IL‐1 β , IL‐6, IL‐8, and TNF‐ α were significantly elevated in patients with severe COVID‐19. [ 49,50 ] As such, we compared the secretion of these cytokines in this alveolus chip under different treatment conditions. Our results showed that SARS‐CoV‐2 infection triggered the increased secretions of cytokines IL‐6 and IL‐8 on the alveolus chip.…”

Nanomedicine strategies to target coronavirus

“…Similarly, the IL-6 antagonists Tocilizumab, a therapeutic also used in rheumatoid arthritis, and Siltuximab, originally applied in multicentric Castleman’s disease, are currently evaluated for their efficacy in COVID-19 [ 225 ]. Besides IL-6, IL-1 is also directly related to CRS and shown to be highly expressed in COVID-19 patients [ 226 ]. Anakinra and Canakinumab are both IL-1 antagonists, which are currently investigated for their efficacy and their potential use for the treatment of COVID-19 [ 227 , 228 ].…”

The Involvement of Innate and Adaptive Immunity in the Initiation and Perpetuation of Sjögren’s Syndrome

“…Their role in allergy and anaphylaxis is well established. However, a great deal of evidence underlines their possible involvement in tissue healing, angiogenesis, and autoimmune exacerbation [ 29 ].…”

“…Mast cells activation through TLR-2 and TLR4 lead to the production of IL-1, TNF-α, IL-33, and chemokines such as C-X-C motif chemokine ligand 1 (CXCL1) and C-X-C motif chemokine ligand 2 (CXCL2), which recruit neutrophilic granulocytes and DCs. The activation of mast cells through IL1R1 and ST2 allows them to interact with T and B cells, interfering with antibody production [ 29 ]. The activation of ST2 on mast cells through IL-33 leads to the production of pro-inflammatory cytokines such as IL-1, IL-6, IL-13 [ 32 ], and induces a TH2 polarization of CD4+ T cells.…”