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 CD39hi 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.
Highlights
Sepsis is a systemic inflammation triggered by pathogens that leads to organ 3 dysfunction (Singer et al, 2016)
Septic B 11 cells failed to suppress bacterial killing by Adora2aΔLyz[2] Mφs (Figure 5H). Taken together, these data support the hypothesis that adenosine derived from CD39+ B cells suppresses the immune response after sepsis, at least in part, through suppression of Mφ microbial killing. 16 We investigated whether B cell-derived adenosine induces IL-10 production 17 in Mφs
The CBX abrogated the inhibitory effect of septic B cells on Mφ bacterial killing and reduced Mφs production of IL-10 (Figures 6K-6M). Collectively, our findings suggest that septic B cells have a metabolic reprogramming toward aerobic glycolysis that feeds mitochondrial tricarboxylic acid (TCA) cycle, supporting their suppressive activity by enhancing production and release of ATP. 18 19 Septic patients have an expansion of CD39+ plasmablast and adenosine accumulation To investigate the clinical relevance of our findings, we collected peripheral blood samples from 21 septic patients and 36 age- and sex-matched healthy controls 23 (HC)
Summary
Sepsis is a systemic inflammation triggered by pathogens that leads to organ 3 dysfunction (Singer et al, 2016). Compelling clinical and experimental studies indicate that sepsis may 8 cause an immunosuppressive state that accounts for increased susceptibility to 9 secondary, mostly opportunistic, infections (Benjamim et al, 2003; Boomer et al, 10 2011; Nascimento et al, 2017; Otto et al, 2011). Potential mechanisms for sepsis-induced immunosuppression include immune cell apoptosis, expansion of the regulatory T (Treg) cell population, and impaired microbial killing by macrophages (Mφs) (Venet and Monneret, 2018). Extracellular adenosine is a signaling molecule that modulates several immunological processes via specific receptors expressed on immune cells (Hasko et al, 2008). The signaling mediated by A2aR augments the production of anti-inflammatory cytokines, inhibits T cell proliferation, suppresses microbial killing by neutrophils and Mφs, and enhances differentiation of M2 Mφs (Hasko et al, 2008; Haskó and Cronstein, 2013)
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