PGE₂production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolutionin vivo

Abstract

Neutrophils are the first immune cells recruited to a site of injury or infection, where they perform many functions. Having completed their role, neutrophils must be removed from the inflammatory site -either by apoptosis and efferocytosis or by reverse migration away from the wound -for restoration of normal tissue homeostasis. Disruption of these tightly controlled physiological processes of neutrophil removal can lead to a range of inflammatory diseases. We used an in vivo zebrafish model to understand the role of lipid mediator production in neutrophil removal. Following tailfin amputation in the absence of macrophages, neutrophillic inflammation does not resolve. This is due to loss of macrophage-dependent production of eicosanoid prostaglandin E2, which drives neutrophil removal via promotion of reverse migration.

Neutrophil–macrophage cooperation and its impact on tissue repair

“…Second, the authors show that in the absence of macrophages, neutrophils did not undergo reverse migration but rather were still found in the wound 12 h after injury . Since then, another study in zebrafish confirmed the importance of macrophages in helping neutrophils to undergo reverse migration, highlighting a role for prostaglandin E2 in this process . The authors showed that rather than direct membrane contact between neutrophils and macrophages, the prostaglandin E2 released by macrophages is required for induction of the migratory behavior of neutrophils observed in reverse migration .…”

“…Since then, another study in zebrafish confirmed the importance of macrophages in helping neutrophils to undergo reverse migration, highlighting a role for prostaglandin E2 in this process . The authors showed that rather than direct membrane contact between neutrophils and macrophages, the prostaglandin E2 released by macrophages is required for induction of the migratory behavior of neutrophils observed in reverse migration . By contrast, in a mouse thermal liver injury model, the depletion of monocytes or macrophages did not affect the clearance of neutrophils from the site of injury, despite the fact that monocytes and macrophages were observed to enter into direct contact with neutrophils during the first 24 h following injury .…”

Bioactive lipid-based therapeutic approach to COVID-19 and other similar infections

“…At low concentrations, PGE2 binds to the high-affinity EP4 receptor and enhances IL-23 production [180], whereas high PGE2 amounts bind to EP2 receptor and suppresses IL-23 release [181,182]. These results account for the dual pro and anti-inflammatory actions of PGE2 P r e p r i n t [183].…”

Untapped Potential: Therapeutically Targeting Eicosanoids and Endocannabinoids in the Lung

“…Interestingly, PGE2 can also promote proresolving functions. Neutrophils stimulated with PGE2 have reduced reactive oxygen species formation, 21 reduced adhesion to endothelial cells, and reduced chemotaxis 22 …”

“…Further complicating matters, PGE2 can also alter the generation of eicosanoids transcellularly, affecting eicosanoid production in neighboring cells. For example, neutrophils exposed to macrophage‐generated PGE2 have reduced LTB4 production 25 and increased lipoxin A4 production, 22 suggesting PGE2 or its metabolites can shift eicosanoid signaling within other cell types.…”