Abstract
Sepsis is a worldwide health priority characterized by the occurrence of severe immunosuppression associated with increased risk of death and secondary infections. Interleukin 10 (IL-10) is a potent immunosuppressive cytokine which plasma concentration is increased in septic patients in association with deleterious outcomes. Despite studies evaluating IL-10 production in specific subpopulations of purified cells, the concomitant description of IL-10 production in monocytes and lymphocytes in septic patients’ whole blood has never been performed. In this pilot study, we characterized IL-10 producing leukocytes in septic shock patients through whole blood intracellular staining by flow cytometry. Twelve adult septic shock patients and 9 healthy volunteers were included. Intracellular tumor necrosis factor-α (TNFα) and IL-10 productions after lipopolysaccharide stimulation by monocytes and IL-10 production after PMA/Ionomycine stimulation by lymphocytes were evaluated. Standard immunomonitoring (HLA-DR expression on monocytes, CD4+ T lymphocyte count) of patients was also performed. TNFα expression by stimulated monocytes was reduced in patients compared with controls while IL-10 production was increased. This was correlated with a reduced monocyte HLA-DR expression. B cells, CD4+, and CD4- T lymphocytes were the three circulating IL-10 producing lymphocyte subsets in both patients and controls. No difference in IL-10 production between patients and controls was observed for B and CD4- T cells. However, IL-10 production by CD4+ T lymphocytes significantly increased in patients in parallel with reduced CD4+ T cells number. Parameters reflecting altered monocyte (increased IL-10 production, decreased HLA-DR expression and decreased TNFα synthesis) and CD4+ T lymphocyte (increased IL-10 production, decreased circulating number) responses were correlated. Using a novel technique for intracellular cytokine measurement in whole blood, our results identify monocytes and CD4+ T cells as the main IL-10 producers in septic patients’ whole blood and illustrate the development of a global immunosuppressive profile in septic shock. Overall, these preliminary results add to our understanding of the global increase in IL-10 production induced by septic shock. Further research is mandatory to determine the pathophysiological mechanisms leading to such increased IL-10 production in monocytes and CD4+ T cells.
Highlights
In 2017, the World Health Assembly and the World Health Organization recognized sepsis as a global health priority [1]
The immunosuppressive state of septic patients was verified by measuring decreased HLA-DR expression on monocytes expressed as a number of antibodies bound per cell (AB/C, see reference for standardized laboratory protocol) and CD4+ T lymphocyte count [11]
This increase was statistically stronger in healthy volunteers (HV) than in patients
Summary
In 2017, the World Health Assembly and the World Health Organization recognized sepsis as a global health priority [1]. While sepsis and septic shock are caused by an excessive activation of the immune system, current data indicate that after a short proinflammatory phase, septic shock patients develop negative regulatory mechanisms aimed at blocking initial hyperimmune activation. In some patients, this may lead to profound immunosuppression involving both innate and adaptive immunity [3]. It is reported that over 70% of total mortality after septic shock occurs in the immunosuppressive phase (i.e., after the first 3 days) [4] This is the rationale behind clinical trials based on adjunctive immunostimulation in sepsis (interferon gamma, human granulocyte-macrophage colonystimulating factor, interleukin 7, anti-PD1/L1 checkpoint inhibitor antibodies) [5]. A better description of sepsisinduced immune alterations is mandatory in order to improve the understanding of sepsis-induced immunosuppression pathophysiology and to identify innovative therapeutic targets and stratification biomarkers
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