Inhibition of mPGES-1 attenuates efficient resolution of acute inflammation by enhancing CX3CL1 expression

Despite the progress to understand inflammatory reactions, mechanisms causing their resolution remain poorly understood. Prostanoids, especially prostaglandin E-2 (PGE(2)), are well-characterized mediators of inflammation. PGE(2) is produced in an inducible manner in macrophages (M phi) by microsomal PGE(2)-synthase-1 (mPGES-1), with the notion that it also conveys pro-resolving properties. We aimed to characterize the role of mPGES-1 during resolution of acute, zymosan-induced peritonitis. Experimentally, we applied the mPGES-1 inhibitor compound III (CIII) once the inflammatory response was established and confirmed its potent PGE(2)-blocking efficacy. mPGES-1 inhibition resulted in an incomplete removal of neutrophils and a concomitant increase in monocytes and M phi during the resolution process. The mRNA-seq analysis identified enhanced C-X3-C motif receptor 1 (CX3CR1) expression in resident and infiltrating M phi upon mPGES-1 inhibition. Besides elevated Cx3cr1 expression, its ligand CX3CL1 was enriched in the peritoneal lavage of the mice, produced by epithelial cells upon mPGES-1 inhibition. CX3CL1 not only increased adhesion and survival of M phi but its neutralization also completely reversed elevated inflammatory cell numbers, thereby normalizing the cellular, peritoneal composition during resolution. Our data suggest that mPGES-1-derived PGE(2) contributes to the resolution of inflammation by preventing CX3CL1-mediated retention of activated myeloid cells at sites of injury.

Automated summary

mPGES-1 plays a crucial role in the resolution of acute inflammation, with its inhibition leading to an increase in inflammatory cell numbers. Inhibition of mPGES-1 was found to enhance CX3CR1 expression and promote the production of CX3CL1, affecting the adhesion and survival of M phi.