EPCR deficiency ameliorates inflammatory arthritis in mice by suppressing the activation and migration of T cells and dendritic cells.

Autor:	Xue M; Sutton Arthritis Research Laboratory, Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia.; Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia., Lin H; Sutton Arthritis Research Laboratory, Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia.; Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia., Liang HPH; Sutton Arthritis Research Laboratory, Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia., Bereza-Malcolm L; Sutton Arthritis Research Laboratory, Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia.; Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia., Lynch T; Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia., Sinnathurai P; Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia., Weiler H; Versiti Blood Research Institute, Versiti, Milwaukee, WI, USA.; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA., Jackson C; Sutton Arthritis Research Laboratory, Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia., March L; Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Sydney Musculoskeletal Health, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia.
Jazyk:	angličtina
Zdroj:	Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2024 Feb 01; Vol. 63 (2), pp. 571-580.
DOI:	10.1093/rheumatology/kead230
Abstrakt:	Objectives: Endothelial protein C receptor (EPCR) is highly expressed in synovial tissues of patients with RA, but the function of this receptor remains unknown in RA. This study investigated the effect of EPCR on the onset and development of inflammatory arthritis and its underlying mechanisms. Methods: CIA was induced in EPCR gene knockout (KO) and matched wild-type (WT) mice. The onset and development of arthritis was monitored clinically and histologically. T cells, dendritic cells (DCs), EPCR and cytokines from EPCR KO and WT mice, RA patients and healthy controls (HCs) were detected by flow cytometry and ELISA. Results: EPCR KO mice displayed >40% lower arthritis incidence and 50% less disease severity than WT mice. EPCR KO mice also had significantly fewer Th1/Th17 cells in synovial tissues with more DCs in circulation. Lymph nodes and synovial CD4 T cells from EPCR KO mice expressed fewer chemokine receptors CXCR3, CXCR5 and CCR6 than WT mice. In vitro, EPCR KO spleen cells contained fewer Th1 and more Th2 and Th17 cells than WT and, in concordance, blocking EPCR in WT cells stimulated Th2 and Th17 cells. DCs generated from EPCR KO bone marrow were less mature and produced less MMP-9. Circulating T cells from RA patients expressed higher levels of EPCR than HC cells; blocking EPCR stimulated Th2 and Treg cells in vitro. Conclusion: Deficiency of EPCR ameliorates arthritis in CIA via inhibition of the activation and migration of pathogenic Th cells and DCs. Targeting EPCR may constitute a novel strategy for future RA treatment. (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
Databáze:	MEDLINE
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