Citrullinated fibrinogen impairs immunomodulatory function of bone marrow mesenchymal stem cells by triggering toll-like receptor

Bone marrow mesenchymal stem cells (BMSC) have been shown to possess immunomodulatory activities, while its role in rheumatoid arthritis (RA) remains unknown. Citrullinated fibrinogen (cfb) has been considered as a specific autoantigen in RA pathogenesis. Our study aims to determine the role of cfb on immunomodulatory function of BMSC. We demonstrated the specific role of toll-like receptor 4 (TLR4)-NFκB pathway in the pro-inflammatory response of BMSC to cfb with increased production of interleukin (IL)-6, IL-8 and chemokine CC motif ligand 2 (CCL2). Moreover, cfb impaired BMSC-mediated suppression of peripheral blood mononuclear cells (PBMC) proliferation and reduced the production of the key immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO) in BMSC. We have uncovered a previously unrecognized role of cfb in interfering BMSC-mediated immunoregulation in RA. Cfb could act as a damage-associated molecule pattern (DAMP) for BMSC and thereby contribute to the propagation of inflammation in RA.