Background/Purpose: Mesenchymal stem cells (MSC) are not only immune-inhibitory cells, and may act as pro-inflammatory cells due to lack of a proper “licensing”. The role of MSC in autoimmune settings of rheumatoid arthritis (RA) has remained to be elucidated. Citrullinated fibrinogen (cfb) has been considered as one of the important autoantigens in RA and contributes to perpetuate the disease. Our study aimed to analyze the responses of bone marrow derived MSC (BMSC) to cfb.

Methods: BMSC were isolated from RA and osteoarthritis (OA) patients and exposed to cfb or native fibrinogen (fb). Proinflammatory cytokines stimulated by cfb were determined by quantitative PCR and ELISA. To evaluate the role of the toll like receptor 4 (TLR4)-NFκB pathway in the induction of cytokines by cfb, parallel experiments were performed using inhibitors of TLR4 or NFκB pathway. To investigate whether BMSC retain their immunosuppressive properties after exposure to cfb, we detected the effects of cfb primed BMSC on proliferation of peripheral blood mononuclear cells (PBMC).

Results: The autoantigen cfb increased the gene expression and protein production of IL-6, IL-8 and CCL2 in BMSC from both RA and OA patients. However, the production of IL-1β and TNFα were unaffected by cfb. Compared with fb, cfb induced significantly higher expression of the pro-inflammatory cytokines (IL-6, IL-8 and CCL2) in these cells. Blocking experiments showed the participation of TLR4-NFκB pathway in the induction of these cytokines. The autoantigen cfb also compromised the ability of BMSC to inhibit PBMC proliferation, as well as, impaired the potency of BMSC to produce the key immunomodulatory molecule indoleamine dioxygenase (IDO).

Conclusion:  Our results suggest that cfb promotes pro-inflammatory responses in BMSC and negatively affects their immunomodulatory functions. Citrullinated fibrinogen may act as a dangerous “licensing” for BMSC and thereby contributing to the propagation of inflammation in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/citrullinated-fibrinogen-promotes-bone-marrow-mesenchymal-stem-cells-to-assume-a-proinflammatory-phenotype/