IL-17-induced inflammation modulates the mPGES-1/PPAR-γ pathway in monocytes/macrophages

Federica Raucci; Anella Saviano; Gian Marco Casillo; Miguel Guerra-Rodriguez; Adel Abo Mansour; Marialuisa Piccolo; Maria Grazia Ferraro; Elisabetta Panza; Valentina Vellecco; Carlo Irace; Francesco Caso; Raffaele Scarpa; Nicola Mascolo; Mohammed Alfaifi; Asif Jilani Iqbal; Francesco Maione

doi:10.1111/bph.15413

IL-17-induced inflammation modulates the mPGES-1/PPAR-γ pathway in monocytes/macrophages

Br J Pharmacol. 2022 May;179(9):1857-1873. doi: 10.1111/bph.15413. Epub 2021 Mar 21.

Authors

Federica Raucci¹, Anella Saviano¹, Gian Marco Casillo¹, Miguel Guerra-Rodriguez², Adel Abo Mansour^{2

3}, Marialuisa Piccolo¹, Maria Grazia Ferraro¹, Elisabetta Panza¹, Valentina Vellecco¹, Carlo Irace¹, Francesco Caso⁴, Raffaele Scarpa⁴, Nicola Mascolo¹, Mohammed Alfaifi³, Asif Jilani Iqbal^{1

2}, Francesco Maione¹

Affiliations

¹ Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
² Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
³ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
⁴ Rheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.

PMID: 33595097
DOI: 10.1111/bph.15413

Abstract

Background and purpose: Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal PGE₂ synthase (mPGES) and PPAR-γ expression are modulated by a variety of inflammatory factors and stimuli. Considering that very little is known about the biological effects promoted by IL-17 in the context of mPGES-1/PPAR-γ modulation, we sought to investigate the contribution of this unique cytokine on this integrated pathway during the onset of inflammation.

Experimental approach: We evaluated effects of PF 9184 (mPGES-1 inhibitor) and troglitazone (PPAR-γ agonist) in vitro, using the mouse macrophage cell line J774A.1. In vivo, the dorsal air pouch model in CD1 mice was used, and inflammatory infiltrates were analysed by flow cytometry. Locally produced cyto-chemokines and PGs were assessed using elisa assays. Western blots were also employed to determine the activity of various enzymes involved in downstream signalling pathways.

Key results: PF 9184 and troglitazone, in a time- and dose-dependent manner, modulated leukocyte infiltration, myeloperoxidase activity, and the expression of COX-2/mPGES-1, NF-кB/IкB-α, and mPTGDS-1/PPAR-γ, induced by IL-17. Moreover, both PF 9184 and troglitazone modulated PG (PGE₂ , PGD₂ , and PGJ₂ ) production, the expression of different pro-inflammatory cyto-chemokines, and the recruitment of inflammatory monocytes, in response to IL-17.

Conclusions and implications: Our data suggest that IL-17 may constitute a specific modulator of inflammatory monocytes during later phases of the inflammatory response. The results of this study show, for the first time, that the IL-17/mPGES-1/PPAR-γ pathway could represent a potential therapeutic target for inflammatory-based and immune-mediated diseases.

Linked articles: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

Keywords: IL-17A; PGE2; PPAR-γ; inflammation; mPGES-1; monocytes/macrophages.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Inflammation / metabolism
Interleukin-17*
Macrophages
Mice
Monocytes / metabolism
PPAR gamma* / metabolism
Prostaglandin-E Synthases / metabolism

Substances

Il17a protein, mouse
Interleukin-17
PPAR gamma
Pparg protein, mouse
Prostaglandin-E Synthases
Ptges protein, mouse