TY  - JOUR
A1  - Rappl, Peter
A1  - Rösser, Silvia
A1  - Maul, Patrick
A1  - Bauer, Rebekka
A1  - Huard, Arnaud
A1  - Schreiber, Yannick
A1  - Thomas, Dominique
A1  - Geisslinger, Gerd
A1  - Jakobsson, Per-Johan
A1  - Weigert, Andreas
A1  - Brüne, Bernhard
A1  - Schmid, Tobias
T1  - Inhibition of mPGES-1 attenuates efficient resolution of acute inflammation by enhancing CX3CL1 expression
T2  - Cell death & disease
N2  - 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 (Mϕ) 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 Mϕ during the resolution process. The mRNA-seq analysis identified enhanced C-X3-C motif receptor 1 (CX3CR1) expression in resident and infiltrating Mϕ 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 Mϕ 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.
KW  - Acute inflammation
KW  - Peritoneal macrophages
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/71016
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-710169
SN  - 2041-4889
N1  - The study was funded by Deutsche Forschungsgemeinschaft (GRK 2336, TP6) and the Swedish Research Council (grant no: 2017-01391). Open Access funding enabled and organized by Projekt DEAL.
VL  - 12
IS  - art. 135
SP  - 1
EP  - 10
PB  - Nature Publishing Group
CY  - London [u.a.]
ER  -