The impact of trauma relevant concentrations of prostaglandin E2 on the anti-microbial activity of the innate immune system.

Abstract

Background: The mechanisms underlying the state of systemic immune suppression that develops following major trauma are poorly understood. A post-injury increase in circulating levels of prostaglandin E₂ (PGE₂) has been proposed as a contributory factor, yet few studies have addressed how trauma influences PGE₂ biology.

Methods: Blood samples from 95 traumatically-injured patients (injury severity score ≥8) were collected across the pre-hospital (≤2 hours), acute (4-12 hours) and subacute (48-72 hours) post-injury settings. Alongside ex vivo assessments of lipopolysaccharide (LPS)-induced cytokine production by monocytes, neutrophil reactive oxygen species production and phagocytosis, serum concentrations of PGE₂ and its scavenger albumin were measured, and the expression of enzymes and receptors involved in PGE₂ synthesis and signalling analysed. Leukocytes from trauma patients were treated with cyclooxygenase (COX) inhibitors (indomethacin or NS-398), or the protein kinase A inhibitor H89, to determine whether injury-induced immune suppression could be reversed by targeting the PGE₂ pathway. The effect that trauma relevant concentrations of PGE₂ had on the anti-microbial functions of neutrophils, monocytes and monocyte-derived macrophages (MDMs) from healthy controls (HC) was examined, as was the effect of PGE₂ on efferocytosis. To identify factors that may trigger PGE₂ production post-trauma, leukocytes from HC were treated with mitochondrial-derived damage associated molecular patterns (mtDAMPs) and COX-2 expression and PGE₂ generation measured.

Results: PGE₂ concentrations peaked in blood samples acquired ≤2 hours post-injury and coincided with significantly reduced levels of albumin and impaired LPS-induced cytokine production by monocytes. Significantly higher COX-2 and phospholipase A₂ expression was detected in neutrophils and/or peripheral blood mononuclear cells isolated from trauma patients. Treatment of patient leukocytes with indomethacin, NS-398 or H89 enhanced LPS-induced cytokine production and neutrophil extracellular trap generation. Exposure to physiological concentrations of PGE₂ suppressed the anti-microbial activity of monocytes, neutrophils and MDMs of HC, but did not influence efferocytosis. In a formyl-peptide receptor-1 dependent manner, mtDAMP treatment significantly increased COX-2 protein expression in neutrophils and monocytes, which resulted in increased PGE₂ production.

Conclusions: Physiological concentrations of PGE₂ suppress the anti-microbial activities of neutrophils, monocytes and MDMs. Targeting the PGE₂ pathway could be a therapeutic approach by which to enhance innate immune function post-injury.