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Inflammation resolution circuits are uncoupled in acute sepsis and correlate with clinical severity.

Abstract

Sepsis is a critical illness characterized by dysregulated inflammatory responses lacking counter-regulation. Specialized pro-resolving mediators are agonists for anti-inflammation and promoting resolution and are protective in preclinical sepsis models. Here, in human sepsis, we mapped resolution circuits for the specialized pro-resolving mediators resolvin D1 and resolvin D2 in peripheral blood neutrophils and monocytes, their regulation of leukocyte activation and function ex vivo, and their relationships to measures of clinical severity. Neutrophils and monocytes were isolated from healthy subjects and sepsis patients by inertial microfluidics and resolvin D1 and resolvin D2 receptor expression determined by flow cytometry. The impact of these resolvins on leukocyte activation was determined by isodielectric separation and leukocyte function by stimulated phagolysosome formation. Leukocyte pro-resolving receptor expression was significantly higher in sepsis. In nanomolar concentrations, resolvin D1 and resolvin D2 partially reversed sepsis-induced changes in leukocyte activation and function. Principal component analyses of leukocyte resolvin receptor expression and responses differentiated sepsis from health and were associated with measures of sepsis severity. These findings indicate that resolvin D1 and resolvin D2 signaling for anti-inflammation and resolution are uncoupled from leukocyte activation in early sepsis and suggest that indicators of diminished resolution signaling correlate with clinical disease severity.

Authors: Jundi B, Lee DH, Jeon H, Duvall MG, Nijmeh J, Abdulnour RE, Pinilla-Vera M, Baron RM, Han J, Voldman J, Levy BD,
Journal: JCI Insight; 2021 Jun 24 . doi:10.1172/jci.insight.148866
Year: 2021
PubMed: PMID: 34166226 (Go to PubMed)