The immunomodulatory role of interleukin (IL)-33 through induction of regulatory B cells (Bregs) and its implication in systemic lupus erythematosus (SLE)

Abstract

IL-33 is a pleiotropic cytokine with various biological effects in immune responses. As part of the IL-1 cytokine family, its potent nature in driving inflammatory processes and pathogenesis in immune-mediated diseases are well established. However, IL-33 was demonstrated to effectively induce the differentiation of peripheral regulatory B cells (Bregs) with unique phenotypes in wild-type C57BL/6 mice. Bregs are immunosuppressive cells that exert vital roles in immune tolerance. Thus, this suggests the previously unknown spectrum of IL-33 in driving immune-regulatory responses, particularly in promoting Breg differentiation.

This thesis, therefore explored and further characterized the possible mechanism of Breg differentiation by IL-33. First, it was found that IL-33 could synergistically induce the in-vitro expansion of Bregs in splenocytes and bone marrow cell culture with CD40-stimulation. Further investigations discovered that the Breg-inducing effect of IL-33 was indirectly through CD4+ T cells and M2-macrophages.

In-vivo tracking study further confirmed that lymphoid origins of IL-33-induced Breg were spleen and bone marrow, but not peritoneal cavity and lymph node. Moreover, exogenous administration of IL-33 in mice significantly upregulated the expression of murine IL-10-competent B cell markers, CD9 and TIM-1, in bone-marrow B cells and promoted their efflux from the bone marrow. Therefore, these may attribute to the IL-33-mediated increase frequency of IL-10+ Bregs in the peripheral blood.

Lastly, the in-vivo regulatory effect of IL-33 was explored in lupus animal models, NZB/W F1 and MRL/lpr strains. It was found that treatment of IL-33 from the age of 6 weeks substantially delayed proteinuria and kidney damage as well as prolonged survival in both NZB/W F1 and MRL/lpr mice. Moreover, incidences of skin lesion and lymphadenopathy were significantly reduced in IL-33-treated MRL/lpr mice as compared to the control group. The observed protective effect of IL-33 was attributed to the increased expression of M2 macrophages-related genes, circulating Breg cells, protective IgM anti-dsDNA antibody and IL-5. The finding that IL-33 exerts a disease suppressing effect in the presence study is in contrast with the previous reports of the disease-promoting roles of IL-33 in SLE and several models of autoimmune diseases, thus, strongly implying the nature of IL-33 as a dichotomous player in both inflammatory and regulatory responses.

Collectively, the studies in this thesis have described the regulatory aspect of IL-33 in inducing the differentiation of Breg cells and its implication in the development of SLE, therefore providing an advanced understanding of the hitherto undetermined regulatory effects of IL-33.