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Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells.

ABSTRACT: Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5'-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a 'calm down' signal. DOI: http://dx.doi.org/10.7554/eLife.02172.001.

SUBMITTER: Yamaguchi H

PROVIDER: S-EPMC3963506 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells.

Yamaguchi Hiroshi H Maruyama Toshihiko T Urade Yoshihiro Y Nagata Shigekazu S

eLife 20140325

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AM ...[more]

PMID: 24668173

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Project description: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 responses. NF-?B signalling pathway mediated the activation of COX2/PGE2 in AC-MSCs. Importantly, in patients with SLE, the plasma PGEM levels increased significantly in those with reduced apoptotic mononuclear cells in peripheral blood after MSC transplantation. INTERPRETATION:Clearance of ACs by MSCs contributes to immunosuppressive function via increasing PGE2 production. These findings reveal a previously unrecognized role of MSC-mediated phagocytosis of ACs in MSC-based immunotherapy. FUND: This study was supported by grants from the Chinese Major International (Regional) Joint Research Project (No. 81720108020), the Jiangsu Province Major Research and Development Program (No. BE2015602) and the Jiangsu Province 333 Talent Grant (BRA2016001). WJ. Chen was supported by the Intramural Research Program of NIH, NIDCR.

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Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells.

Publications

Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells.

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