Involvement of IL-33 in the Pathophysiology of Systemic Lupus Erythematosus: Review

Abstract

IL-33 is a newly discovered cytokine displaying pleiotropic localizations and functions. More specifically, it also functions as an alarmin, following its release from cells undergoing cell death or necrosis, to alert the innate immune system. The role of IL-33 has been underlined in several inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE). The expressions of IL-33 as well as its receptor, ST2, are significantly upregulated in SLE patients and in patients with lupus nephritis. This review discusses the involvement of IL-33 in the pathology of SLE.

Keywords: IL-33; alarmins; autoimmune disease; cytokines; inflammation; innate immunity; systemic lupus erythematosus.

Figure 1

IL-33/ST2 axis signaling.

Figure 2

The dichotomous role of the IL-33/ST2 axis in inflammatory diseases. IL-33 is passively released by dying cells in the extracellular compartment where it exerts its functions through the receptor ST2. ST2 is found in a wide variety of myeloid and lymphoid cells where it can induce either inflammatory or pro-inflammatory responses depending on the immunological context. The IL-33/ST2 axis induces the secretion of type 2 cytokines such as IL-4 and IL-13 by eosinophils and mast cells, and IL-5 and IL-13 by ILC2 and Th2 cells. IL-33/ST2 mediates the activation of NK cells, leading to the production of IFN-γ and IL-12. Besides the secretion of IL-1 and IL-6, activated DCs induce a Th2 polarization of CD4+ T cells. IL-33/ST2 activation can also activate Th1 cells and CD8+ T cells, leading to type 1 cytokine secretion and cytotoxic activity. On the other hand, IL-33/ST2 also induces IL-2 secretion by mast cells and dendritic cells, leading to Treg expansion. In addition, ST2 has been demonstrated on Treg, Breg and M2 macrophages, leading to anti-inflammatory cytokine production (IL-10, TGF-beta). ILC2 and Treg are also a source of AREG, which promotes tissue healing. Abbreviations: AREG: amphiregulin; Breg: regulatory B cells; DCs: dendritic cells; IFN-γ: interferon gamma; IL-: interleukin; ILC2: innate Lymphoid Cells type 2; NK: natural killer cells; ST2: receptor suppression of tumorigenicity 2; TGF-β: transforming growth factor beta; Th1: type 1 helper cells; Th2: type 2 helper cells; TNF tumor necrosis factor; Treg: regulatory T cells.

Figure 3

Hypothesis of the involvement of the IL-33/ST2 axis in the pathogenesis of systemic lupus erythematosus. The dual role of the IL-33/ST2 axis can be seen as a balance between pro-inflammatory and anti-inflammatory effects. Unknown factors (3 questions marks in the figure) can influence this balance, skewing the immune response toward either pro- or anti-inflammatory states. In genetically susceptible subjects, environmental stimuli such as viruses, UV light and stress may trigger cell death and necrosis of the epithelial barrier, leading to passive release of IL-33, apoptotic blebs and exposure of autoantigens, ultimately leading to the formation of ICs. The products of cell damage, together with ICs, activate neutrophils to produce NETs that complex with IL-33 to activate DCs via their ST2 receptor, leading to a potent type I IFN secretion that contributes to the IFN signature of SLE. In addition, IL-33 also directly activates ST2 expressed by DCs, leading to the Th2 polarization of CD4+ T cells. IL-33 induces BAFF secretion by bone marrow stromal cells and possibly other, but not yet identified, cells that induce B cell differentiation into plasma cells, further contributing to germinal center formation and IC formation. Under certain conditions, probably in the early phase of the disease, the anti-inflammatory effects of IL-33 are dominant. sST2 levels are elevated to counteract IL-33 actions. IL-33/ST2 also induces IL-2 secretion by mast cells and dendritic cells, leading to Treg expansion. In addition, ST2 has been demonstrated on Treg, Breg and M2 macrophages, leading to anti-inflammatory cytokine production (IL-10, TGF-beta). Finally, ILC2 and Treg are also a source of AREG, which promotes tissue healing. Abbreviations: AREG: amphiregulin; BAFF: B-cell activating factor; Breg: regulatory B cells; BM: bone marrow; DCs: dendritic cells; IC: immune complexes; IFN-γ: interferon gamma; IL-: interleukin; ILC2: innate Lymphoid Cells type 2; NETs: neutrophil extracellular traps; NP: neutrophils; sST2: soluble ST2; ST2: receptor suppression of tumorigenicity 2; TGF-β: transforming growth factor beta; Th2: type 2 helper cells; TNFα: tumor necrosis factor alpha; Treg: regulatory T cells; UV: ultraviolet; ⊥: inhibit; blue and red ↓: induce/activate.