Affiliation:
1. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University Nanjing China
2. Department of Rheumatology and Immunology Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University Nanjing China
3. Department of Rheumatology and Immunology Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine Nanjing China
Abstract
AbstractAlthough 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.
Funder
Medical Science and Technology Development Foundation, Nanjing Municipality Health Bureau
National Natural Science Foundation of China
Subject
Immunology,Immunology and Allergy