Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2

作者：Zhuoya Zhang, Saisai Huang, Shufang Wu, Jingjing Qi, Wenchao Li, Shanshan Liu, Cong Yan, Hongwei Chen, Liwei Lu, Songtao Shi, Dandan Wang, Wanjun Chen, Lingyun Sun · 发表于：EBioMedicine · 年份：2019 · DOI：10.1016/j.ebiom.2019.06.016 · 被引用次数：97 · 研究领域：Phagocytosis and Immune Regulation、Mesenchymal stem cell research、IL-33, ST2, and ILC Pathways

Background Defective clearance of apoptotic cells (ACs) has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) exhibit promising therapeutic effects on SLE, but whether MSCs phagocytose ACs and contributes to the underlying mechanism in the treatment of SLE remain unknown. Methods Human umbilical cord (UC) MSCs were co-cultured with ACs, and the engulfment of ACs by MSCs was either detected by flow cytometry or observed under confocal laser scanning microscope. Peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) were cultured in MSC conditioned medium (MCM) or MSC exposed to ACs (AC-MSC) conditioned medium (ACMCM), and then CD4 + T cell proliferation was detected. Soluble factors including prostaglandin (PG)E2 in the supernatants of MSCs and AC-MSCs, as well as in the mouse peritoneal lavage fluids (PLF) were determined by enzyme-linked immunosorbent assay (ELISA). Cyclooxygenase (COX)2 inhibitors and siRNA transfection were utilized to determine the function of COX2/PGE2 in AC-MSC-mediated immunosuppression. PGE2 metabolites (PGEM) in the plasma of SLE patients were measured before and 24 h after MSC transplantation respectively. Findings Human UC MSCs possessed the ability to engulf ACs. AC-MSCs increased MSC-mediated suppression of CD4 + T cell proliferation compared to MSCs alone. Mechanistically, ACs stimulated MSCs to express COX2 and consequently produced PGE2 that inhibited T cell r...