Proteasome inhibition ameliorates experimental Sjögren’s syndrome by suppressing Th17 and B cell responses

Abstract

Abstract Primary Sjögren’s syndrome (SS) is a chronic autoimmune disease that mainly affects salivary and lacrimal glands. Currently, there is a lack of effective therapies for SS patients. Increasing evidence indicates that Bortezomib (BTZ), the first proteasome inhibitor approved for treating multiple myeloma, shows beneficial effects in treating lupus. Although clinical findings have revealed increased expression of proteasome in SS patients, it remains unclear whether proteasome inhibition is an effective approach for treating SS. In this study, we evaluated the therapeutic effects of BTZ on experimental SS (ESS) mouse model. Mice were immunized with proteins extracted from salivary glands (SG) to induce ESS and received either vehicle or BTZ treatment. Compared with vehicle-treated counterparts, BTZ-treated mice displayed markedly higher saliva flow rates and ameliorated tissue destructions accompanied with less lymphocytes infiltration in SG. Notably, mice with BTZ treatment showed significantly decreased Th17 but not Th1 responses, and reduced germinal center B cells and plasma cells in peripheral lymphoid organs. In culture, BTZ treatment significantly suppressed Th17 cells differentiation and proliferation. Moreover, adoptively transferred naïve CD4 T cells differentiated into Th17 cells and induced salivary dysfunction in immunized Il17a−/− mice. However, the BTZ-treated recipient mice exhibited suppressed Th17 responses with ameliorated reduction in salivary secretion. Taken together, our findings have shown that BTZ treatment can suppress Th17 and B cell responses and effectively ameliorate ESS development in mice, which may contribute to the validation of BTZ as a promising candidate for treating SS.