Polymorphonuclear myeloid-derived suppressor cells play a proinflammatory role via TNF-α+ B cells through BAFF/BTK/NF-κB signalling pathway in the pathogenesis of collagen-induced arthritis mice.

Although various studies have been performed on the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in RA, the results were conflicting. Here we were trying to clarify the role of PMN-MDSCs in the pathogenesis of RA and its specific mechanisms. We detected the frequencies and counts of PMN-MDSCs, TNF-α+ B cells and Ki67+ B cells in spleen and inflamed joints of collagen-induced arthritis (CIA) mice using flow cytometry. The pathological role of PMN-MDSCs was examined by anti-Ly6G neutralizing antibodies against PMN-MDSCs or adoptive transfer of PMN-MDSCs. And the modulation of PMN-MDSCs on B cells was conducted by coculture assays, RNA-Seq, RT-qPCR, and so on. The mechanism of BAFF regulating B cells was verified through western blot and flow cytometry. PMN-MDSCs accumulated in the spleen and joints of CIA mice. PMN-MDSCs depletion could alleviate the arthritis severity, which was accompanied by decreased TNF-α secretion and proliferation of B cells. And its adoptive transfer also facilitated disease progress. Furthermore, PMN-MDSCs from CIA mice had higher expression level of BAFF, which regulated TNF-α expression, proliferation and apoptosis of B cells in vitro. What's more, BAFF promoted phosphorylation of BTK/NF-κB signalling pathway. And Ibrutinib (BTK inhibitor) could reverse the effect of BAFF on TNF-α expression of B cells. Our study suggested that PMN-MDSCs enhanced disease severity of CIA and manipulated TNF-α expression, proliferation and apoptosis of B cells via BAFF, furthermore, BAFF promoted TNF-α expression through BTK/NF-κB signalling pathway, which demonstrated a novel pathogenesis of PMN-MDSCs in CIA.