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.

Keywords: IL-1; IL-33; Sjögren syndrome; cytokine; immunity; inflammation; mast cell.

Figure 1

Lymphocyte infiltration in primary Sjogren’s syndrome (pSS) xerostomia (biopsy). (The tissue was coloured with Toleudine blue 0.1% then was analysed under optical miscroscopy magnification ×10).

Figure 2

Xerophthalmia and xerostomia glands in primary Sjogren’s syndrome (pSS) inflammation release pro-inflammatory cytokines IL-1 and IL-33 which activate mast cells (MCs) to produce IL-1 family members exacerbating inflammation in pSS. In this figure, we show the biosynthesis of IL-1 and IL-33 which are mediators of systemic inflammation in primary and secondary Sjogren’s syndrome. IL: interleukin; TLR: Toll-like receptor; ST: soluble transmembrane; MyD: Myeloid differentiation primary response; IRAK: IL-1 receptor-associated kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells.

Figure 3

The antigenic activation of Toll-like receptor (TLR) and/or interleukin (IL)-1R receptor with IL-1 leads to the generation of IL-1 mRNA with the production of pro-IL-37, which by means of a caspase-1 causes the release of IL-37 mature in the nucleus. Outside the cell, pro-IL-37 reacts with an unknown protease to produce the mature IL-37. Both, pro-IL-37 and the mature form are active in inhibiting inflammation in Sjogren’s syndrome. Here we confirm the anti-inflammatory activity of IL-37 in several diseases, including Sjogren’s syndrome. TLR: Toll-like receptor; IL: interleukin; mRNA: messenger ribonucleic acid; Ag: antigen.

Figure 4

In this figure, we show the mechanism of IL-37 exerting immuno-inhibitory function in Sjogren’s syndrome inflammation. IL: interleukin; mRNA: messenger ribonucleic acid.