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

Peter Rappl,Arnaud Huard,Tobias Schmid,Patrick Maul,Bernhard Brüne,Silvia Rösser,Rebekka Bauer,Andreas Weigert,Per-Johan Jakobsson,Yannick Schreiber,Gerd Geisslinger,Dominique Thomas

doi:10.1038/s41419-021-03423-2

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 (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.

Highlights

Inflammatory responses are essential for an effective host defense against pathogenic threats such as invading bacteria or viruses[1,2]
Injection of zymosan (5 mg/kg), and inhibited prostaglandin E2 (PGE2) synthesis by daily i.p. injections of the selective microsomal PGE2 synthase-1 (mPGES-1) inhibitor compound III (CIII) (25 mg/kg)[26] once the inflammatory response was established for 24 h (Fig. 1A)
Since Itgb[7] ranged high among the differentially expressed genes (DEGs) upregulated at day 6 upon CIII-treatment (Fig. 2G), we addressed changes in Mφ adhesion to fibronectin (FN) in response to CX3CL1

Summary

Introduction

Inflammatory responses are essential for an effective host defense against pathogenic threats such as invading bacteria or viruses[1,2]. Rappl et al Cell Death and Disease (2021)12:135 interfering with early inflammatory reactions alters resolution as well[11,13] Along these lines, recent studies indicated that the well-established pro-inflammatory lipid mediator prostaglandin E2 (PGE2)[14] bears proresolving properties[15,16,17,18,19,20]. Recent studies indicated that the well-established pro-inflammatory lipid mediator prostaglandin E2 (PGE2)[14] bears proresolving properties[15,16,17,18,19,20] This is of interest, since nonsteroidal anti-inflammatory drugs (NSAIDs), which are the main class of non-prescribed, over the counter antiinflammatory drugs, target cyclooxygenases to inhibit the production of prostanoids, most notably PGE221,22. More specific inhibitors of PGE2 production have recently been developed to target the terminal synthase active under inflammatory conditions, i.e. the microsomal PGE2 synthase-1 (mPGES-1)[23,24,25]

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Conclusion