期刊
JOURNAL OF INFLAMMATION RESEARCH
卷 15, 期 -, 页码 6813-6829出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/JIR.S359775
关键词
rheumatoid arthritis; bone marrow; CTLA-4-Fc; indoleamine 2; 3-dioxygenase; CD4+Foxp3+; monocytes
类别
资金
- National Institute of Geriatrics, Rheumatology, and Rehabilitation from the Polish Ministry of Science and Higher Education [S/9]
- National Science Centre [2018/30/E/NZ5/00104]
This study sheds light on immunosuppressive aspects present or induced in the bone marrow, and confirms the potential of IDO-mediated pathways in the periphery, which could be promising candidates for therapeutic strategies in RA.
Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease with systemic inflammation finally resulting in damaged joints. One of the RA development models suggests bone marrow (BM) as a place of inflammation development further leading to disease progression. We aimed to investigate the potential of CTLA-4-Fc molecule in inducing tolerogenic milieu in BM measured as indoleamine 2,3-dioxygenase (IDO) expression, CD4+Foxp3+ Treg induction, and T cell activation control. The expression of IDO-pathway genes was also examined in monocytes to estimate the tolerogenic potential in the periphery.Methods: Bone marrow mononuclear cells (BMMC) were stimulated by pro-inflammatory cytokines and CTLA-4-Fc. Next IDO expression, CD4+CD69+ and CD4+Foxp3+ percentage were estimated by PCR and FACS staining, respectively. Enzymatic activity of IDO was confirmed by HPLC in BM plasma and blood plasma. Genes expressed in IDO-pathway were analyzed by NGS in peripheral monocytes isolated from RA patients and healthy controls.Results: We found that CTLA-4-Fc and IFN-gamma stimulation results in IDO production by BMMC. CTLA-4-Fc induced tryptophan catabolism can inhibit mitogen-induced CD4+ T cells activation without influencing CD8+ cells, but did not control CD25 nor Foxp3 expression in BM cells. Significantly higher expression of selected IDO-pathway genes was detected on peripheral monocytes isolated from RA as compared to healthy controls.Conclusion: This study sheds light on some immunosuppression aspects present or induced in BM. The potential of IDO-mediated pathways were confirmed in the periphery, what may represent the promising candidates for therapeutic strategies in RA.
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