The role of IL-25 in the pathogenesis of Sjögren's syndrome

Abstract

Interleukin-25 (IL-25) is a crucial cytokine belonging to the IL-17 cytokine family involved in host defense responses and inflammatory diseases. IL-25 has been implicated as an anti-inflammatory as well as pro-inflammatory cytokine in the pathogenesis of Th17-dominated diseases. Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by the inflammation in salivary glands (SGs) and lacrimal glands (LGs), leading to dry eye and dry mouth symptom. Patients with pSS exhibit immunologic features of enhanced B cell activation, including increased levels of serum autoantibodies and autoantibody-secreting plasma cells detected within the SGs. Previous studies have revealed that IL-25 is involved in the development of SS. Although the effect of IL-25 on innate immune cells, tissue cells and T cells have been studied, its role in regulating B cell functions in the pathogenesis of SS still remains unknown. This study aimed to examine the effect of IL-25 on B cell differentiation and function in the pathogenesis of SS in mice with experimental SS.

First, increased levels of IL-25 expression were detected in labial biopsy samples of pSS patients. In peripheral blood mononuclear cells (PBMCs) from pSS patients and spleens (SPs) from experimental SS (ESS) mice, plasma cells (PCs) showed the highest expression level of IL-25 receptor (IL-17RB) among B cell subpopulations and were significantly increased compared with healthy controls. In addition, enhanced infiltrations of IL-17RB+ PCs with stronger ability to secret autoantibodies were detected in the SGs of pSS patients and ESS mice, which were positively correlated with disease severity.

Next, adoptive transfer of IL-17RB+ PCs derived from ESS mice into immunodeficient Rag2-/- mice triggered salivary gland tissue damage and IgG deposition in SGs. In addition, Rag2-/- mice transferred with IL-17RB+ PCs showed significantly higher levels of autoantibodies in the serum and significantly increased autoantibody-secreting cells in the SPs, compared with Rag2-/- mice transferred with IL-17RB- PCs.

Further, in vitro culture of IL-25 enhanced the survival capacity of purified PCs from ESS mice and IL-17RB+ plasma cell line. Moreover, IL-25 specifically increased the level of myeloid cell lymphoma-1 (Mcl-1) in IL-17RB+ PCs from ESS mice through the activation of STAT3 signaling pathway to maintain PC survival. Notably, the blockade of STAT3 dramatically decreased the level of Mcl-1 upon IL-25 stimulation.

Finally, neutralization of IL-25 in SGs of ESS mice by cannulation therapy restored salivary gland function by recovering saliva secretion, meanwhile decreasing IL-25 level in SGs and reducing infiltrations of PCs in SGs of ESS mice, which ameliorated disease development in SGs of ESS mice.

In this study, I have demonstrated that PCs show increased levels of IL-25 receptor expression in the pathogenesis of ESS and that IL-25 significantly enhances PCs survival via pSTAT3-Mcl-1 pathway. Neutralization of IL-25 ameliorates disease progression by reducing PC infiltrations, decreasing IL-25 level in SGs and restored salivary gland function in ESS mice. In summary, these results have identified a novel function of IL-25 in regulating B cell function and indicate the promising therapeutic effect of IL-25 blockade for the treatment of SS.