Abstract
Bacterial sepsis is a major cause of mortality resulting from inadequate immune responses to systemic infection. Effective immunomodulatory approaches are urgently needed but it has remained elusive, which targets might be suitable for intervention. Increased expression of the G-protein-coupled receptor GPR43, which is known to govern intestinal responses to acetate, has been associated with sepsis patient survival but the mechanisms behind this observation have remained unclear. We show that elevated serum acetate concentrations prime neutrophils in a GPR43-dependent fashion, leading to enhanced neutrophil chemotaxis, oxidative burst, cytokine release and upregulation of phagocytic receptors. Consequently, acetate priming improved the capacity of human neutrophils to eliminate methicillin-resistant Staphylococcus aureus. Acetate administration increased mouse serum acetate concentrations and primed neutrophils. Notably, it rescued wild-type mice from severe S. aureus sepsis and reduced bacterial numbers in peripheral organs by several magnitudes. Acetate treatment improved the sepsis course even when applied several hours after onset of the infection, which recommends GPR43 as a potential target for sepsis therapy. Our study indicates that the severity of sepsis depends on transient neutrophil priming by appropriate blood acetate concentrations. Therapeutic interventions based on GPR43 stimulation could become valuable strategies for reducing sepsis-associated morbidity and mortality.
Highlights
Bacterial sepsis is a major cause of mortality resulting from inadequate immune responses to systemic infection
To analyze if GPR43 can shape neutrophil reactive oxygen species (ROS) production, we monitored oxidative burst upon GPR43 activation by the natural ligand acetate or the synthetic specific agonist 4-chloro-α-(1-methylethyl)-N-2-thiazolylbenzeneacetamide) (4CMTB)[30]
While GPR43 activation failed to induce ROS generation in the absence of other stimuli, it enhanced the oxidative burst induced by bacterial ligands of FPR1 (Fig. 1a–c and Supplementary Fig. 1a) or FPR2 (Supplementary Fig. 1a), by endogenous ligands for plateletactivating factor or C5a receptors (PAFR or C5aR, respectively) (Supplementary Fig. 1a), or by live, serum-opsonized S. aureus cells (Supplementary Fig. 1b, c)
Summary
Bacterial sepsis is a major cause of mortality resulting from inadequate immune responses to systemic infection. Acetate administration increased mouse serum acetate concentrations and primed neutrophils. It rescued wild-type mice from severe S. aureus sepsis and reduced bacterial numbers in peripheral organs by several magnitudes. Our study indicates that the severity of sepsis depends on transient neutrophil priming by appropriate blood acetate concentrations. 1234567890():,; Bacterial infections represent a major cause for severe diseases whose therapy is complicated by worldwide increasing rates of antibiotic resistance[1]. The therapy of sepsis has not made major progress in the last decades and new approaches that modulate systemic immune responses in suitable ways are urgently needed[8]
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