1. Sepsis expands a CD39 + plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity.
- Author
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Nascimento DC, Viacava PR, Ferreira RG, Damaceno MA, Piñeros AR, Melo PH, Donate PB, Toller-Kawahisa JE, Zoppi D, Veras FP, Peres RS, Menezes-Silva L, Caetité D, Oliveira AER, Castro ÍMS, Kauffenstein G, Nakaya HI, Borges MC, Zamboni DS, Fonseca DM, Paschoal JAR, Cunha TM, Quesniaux V, Linden J, Cunha FQ, Ryffel B, and Alves-Filho JC
- Subjects
- Adenosine metabolism, Animals, Antigens, CD metabolism, Apyrase metabolism, Cellular Reprogramming immunology, Macrophages metabolism, Mice, Plasma Cells metabolism, Receptor, Adenosine A2A immunology, Receptor, Adenosine A2A metabolism, Sepsis metabolism, Adenosine immunology, Antigens, CD immunology, Apyrase immunology, Immune Tolerance immunology, Macrophages immunology, Plasma Cells immunology, Sepsis immunology
- Abstract
Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39
hi B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39hi plasmablasts and adenosine accumulation. Our study reveals CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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