Polymorphonuclear myeloid-derived suppressor cells play a
proinflammatory role via TNF-α + B cells through BAFF/BTK/NF-B signaling
pathway in the pathogenesis of collagen-induced arthritis mice
Abstract
Objectives: 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. Methods: We detected the frequencies and counts of
PMN-MDSCs, TNF- + B cells, and Ki67
+ B cells in spleens 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, etc. The mechanism of BAFF regulating B cells was
verified through Western Blot and flow cytometry. Results:
PMN-MDSCs accumulated in the spleens and joints of CIA mice. PMN-MDSCs
depletion could alleviate the arthritis severity, which was accompanied
by decreased TNF- 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- expression, proliferation and apoptosis of B cells
in vitro. What’s more, BAFF promoted phosphorylation of BTK/NF-B
signaling pathway. And Ibrutinib (BTK inhibitor) could reverse the
effect of BAFF on TNF- expression. Conclusions: Our study
suggested that PMN-MDSCs enhanced disease severity of CIA and
manipulated TNF- expression, proliferation and apoptosis of B cells via
BAFF, furthermore, BAFF promoted TNF- expression through BTK/NF-B
signaling pathway, which demonstrated a novel pathogenesis of PMN-MDSC
in CIA.