Disruption of GPR35 Signaling in Bone Marrow-Derived Cells Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice.

Roland Baumgartner,Daniel F. J. Ketelhuth,Felipe B. Casagrande,Randi B. Mikkelsen,Maria J. Forteza,Konstantinos A. Polyzos,Martin Berg,Thue W. Schwartz,Aastha Arora,Siv A. Hjorth

doi:10.3390/metabo11070411

Abstract

G-protein-coupled receptor-35 (GPR35) has been identified as a receptor for the tryptophan metabolite kynurenic acid (KynA) and suggested to modulate macrophage polarization in metabolic tissues. Whether GPR35 can influence vascular inflammation and atherosclerosis has however never been tested. Lethally irradiated LdlrKO mice were randomized to receive GPR35KO or wild type (WT) bone marrow transplants and fed a high cholesterol diet for eight weeks to develop atherosclerosis. GPR35KO and WT chimeric mice presented no difference in the size of atherosclerotic lesions in the aortic arch (2.37 ± 0.58% vs. 1.95 ± 0.46%, respectively) or in the aortic roots (14.77 ± 3.33% vs. 11.57 ± 2.49%, respectively). In line with these data, no changes in the percentage of VCAM-1+, IAb + cells, and CD3+ T cells, as well as alpha smooth muscle cell actin expression, was observed between groups. Interestingly, the GPR35KO group presented a small but significant increase in CD68+ macrophage infiltration in the plaque. However, in vitro culture experiments using bone marrow-derived macrophages from both groups indicated that GPR35 plays no role in modulating the secretion of major inflammatory cytokines. Our study indicates that GPR35 expression does not play a direct role in macrophage activation, vascular inflammation, and the development of atherosclerosis.

Highlights

Cardiovascular diseases (CVDs), including myocardial infarction and stroke, are the leading cause of death worldwide [1]
Our study indicates that G-protein-coupled receptor-35 (GPR35) expression does not play a direct role in macrophage activation, vascular inflammation, and the development of atherosclerosis
Recent research has changed this view and shown that many metabolites can act as signaling molecules, for example interacting with metabolite sensing G-protein-coupled receptors (GPCRs) [4]

Summary

Introduction

Cardiovascular diseases (CVDs), including myocardial infarction and stroke, are the leading cause of death worldwide [1]. The most common cause of CVDs is atherosclerosis, a chronic inflammatory disease affecting large- and medium-sized arteries. Atherosclerosis is initiated by the retention and accumulation of low-density lipoprotein (LDL) in the subendothelial space, triggering a maladaptive vascular and immune cell responses [2]. Novel insights into the processes driving inflammation have revealed that microenvironmental changes in metabolism can control immune cell functions. Immunometabolism, which is how this field is recognized, has been implicated in several pathophysiological processes, including metabolic disorders, cancer, autoimmunity, as well as atherosclerosis [3]. For a very long time, metabolites have been considered as just “fuels”, energy sources or building blocks, in cellular metabolic processes. Recent research has changed this view and shown that many metabolites can act as signaling molecules, for example interacting with metabolite sensing G-protein-coupled receptors (GPCRs) [4]

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