Systemic inflammatory response syndrome–related lymphopenia is associated with adenosine A1 receptor dysfunction

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

Mazar, Julia¹  Haviv, Yosef S.⁴  Cohen, Yair⁴  Chaimovitz, Cidio⁶  Eini-Rider, Hadar⁶  Douvdevani, Amos⁷  Naamani, Oshri⁷ 

[1] ..Department of Nephrology, Faculty of Health Sciences, Ben‐..Laboratory of Hematology, Faculty of Health Sciences, Ben‐Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben‐Department of Nephrology, Faculty of Health Sciences, Ben‐Gurion University of the Negev and Soroka University Medical Center, Beer‐Sheva, Israel

关键词: sepsis;    G‐;    coupled receptor;    IL‐;    15;    cAMP;   

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

SIRS is associated with lymphopenia, and prolonged lymphopenia of septic patients has been associated with increased mortality risk. We hypothesize that elevated adenosine during SIRS down-regulates G_i-coupled A₁R, which signals an effect that sensitizes a cAMP-dependent lymphotoxic response. In this study, we evaluate the role of adenosine in SIRS-mediated lymphopenia and impaired IL-15 production. Cecal ligation and puncture was used to induce sepsis-associated SIRS in mice. BMDCs were cultured and used to measure the effect of adenosine on IL-15. We found that A₁R mRNA levels were significantly down-regulated and A₁R-dependent G_i activity was abolished in T cells of septic mice. In accordance, cAMP was elevated in isolated T cells from cecal ligation and puncture compared with sham-treated mice. Similar to septic mice, leukopenia was evident in sham A₁R-KO mice, after treatment with the A₁R antagonist (8-cyclopentyl-1,3-dipropylxanthine), or after A₁R desensitization. In contrast, A_2AR-KO mice were protected from leukopenia. In addition, we observed that septic A₁R-KO mice exhibited low IL-15 levels. Cultured BMDC agonists of A_2AR and A_2BR inhibited IL-15 production and adenosine blocked IL-15–dependent proliferation of cytotoxic T cells that were cocultured with stimulated BMDCs. To conclude, we suggest that SIRS-associated lymphopenia is initiated by A₁R desensitization and adenosine-mediated inhibition of IL-15 production is part of the mechanism that accounts for the delay in leukopenia recovery in patients with severe sepsis. Interference with adenosine signaling may thus be potentially beneficial for septic patients with leukopenia.

【 授权许可】

CC BY