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  4. Inhibition of mPGES-1 attenuates efficient resolution of acute inflammation by enhancing CX3CL1 expression
 
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2021
Journal Article
Title

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

Abstract
Despite the progress to understand inflammatory reactions, mechanisms causing their resolution remain poorly understood. Prostanoids, especially prostaglandin E2 (PGE2), are well-characterized mediators of inflammation. PGE2 is produced in an inducible manner in macrophages (Mf) by microsomal PGE2-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 PGE2-blocking efficacy. mPGES-1 inhibition resulted in an incomplete removal of neutrophils and a concomitant increase in monocytes and Mf during the resolution process. The mRNA-seq analysis identified enhanced C-X3-C motif receptor 1 (CX3CR1) expression in resident and infiltrating Mf 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 Mf 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 PGE2 contributes to the resolution of inflammation by preventing CX3CL1-mediated retention of activated myeloid cells at sites of injury.
Author(s)
Rappl, P.
Rösser, S.
Maul, P.
Bauer, R.
Huard, A.
Schreiber, Y.
Thomas, D.
Geisslinger, G.
Jakobsson, P.-J.
Weigert, A.
Brüne, B.
Schmid, T.
Journal
Cell death & disease. Online journal  
Open Access
DOI
10.1038/s41419-021-03423-2
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Language
English
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP  
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