The G2A Receptor Controls Polarization of Macrophage by Determining Their Localization Within the Inflamed Tissue.

Katharina Kern,Jennifer Cohnen,Stefan Hohmann,Gerd Geisslinger,Stephan M G Schäfer,Bernhard Brüne,Klaus Scholich,Tabea Osthues,Neda Tarighi,Andreas Weigert,Sandra Pierre,Marco Sisignano,Nerea Ferreiros

doi:10.3389/fimmu.2018.02261

Abstract

Macrophages are highly versatile cells, which acquire, depending on their microenvironment, pro- (M1-like), or antiinflammatory (M2-like) phenotypes. Here, we studied the role of the G-protein coupled receptor G2A (GPR132), in chemotactic migration and polarization of macrophages, using the zymosan-model of acute inflammation. G2A-deficient mice showed a reduced zymosan-induced thermal hyperalgesia, which was reversed after macrophage depletion. Fittingly, the number of M1-like macrophages was reduced in the inflamed tissue in G2A-deficient mice. However, G2A activation was not sufficient to promote M1-polarization in bone marrow-derived macrophages. While the number of monocyte-derived macrophages in the inflamed paw was not altered, G2A-deficient mice had less macrophages in the direct vicinity of the origin of inflammation, an area marked by the presence of zymosan, neutrophil accumulation and proinflammatory cytokines. Fittingly neutrophil efferocytosis was decreased in G2A-deficient mice and several lipids, which are released by neutrophils and promote G2A-mediated chemotaxis, were increased in the inflamed tissue. Taken together, G2A is necessary to position macrophages in the proinflammatory microenvironment surrounding the center of inflammation. In absence of G2A the macrophages are localized in an antiinflammatory microenvironment and macrophage polarization is shifted toward M2-like macrophages.

Highlights

Macrophages are heterogeneous immune cells that exhibit a high plasticity and can be roughly classified by two polarized end states named M1 and M2 [1]
We observed a significantly decreased thermal hyperalgesia in G2A−/− mice 24 h after zymosan-injection (Figure 1A), a time point where the inflamed tissue is characterized by a strong infiltration of monocyte-derived macrophages [26, 28]
FACS analysis of the inflamed paws showed that the clodronate-treatment decreased the number of monocyte-derived macrophages in the inflamed paw 24 h after zymosan injection while the number of CD11c+/CD11b+positive dendritic cells was not altered (Figure S1) suggesting that macrophages mediate the antinociceptive effect in G2A-deficent mice

Summary

INTRODUCTION

Macrophages are heterogeneous immune cells that exhibit a high plasticity and can be roughly classified by two polarized end states named M1 (proinflammatory) and M2 (antiinflammatory) [1]. M1-like macrophages, which were polarized by stimuli such as interferon γ (IFNγ) or toll-like receptor (TLR)-ligands, exhibit strong antimicrobial capacities by producing high levels of proinflammatory mediators, whereas M2-like macrophages participate in clearance of cell debris and efferocytosis during resolution [1, 6]. We studied the role of G2A in polarization of macrophages during an acute zymosan-induced inflammation, a common model for toll-like receptor-2-mediated inflammation, which mediates immune responses against a wide array of infectious agents including gram-positive bacteria, virus, protozoa, and fungi [22].

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION