Abstract

G protein-coupled receptors (GPCRs) are key regulatory proteins of immune cell function inducing signaling in response to extracellular (pathogenic) stimuli. Although unrelated, hydroxycarboxylic acid receptor 3 (HCA(3)) and GPR84 share signaling via G alpha(i/o) proteins and the agonist 3-hydroxydecanoic acid (3HDec). Both receptors are abundantly expressed in monocytes, macrophages and neutrophils but have opposing functions in these innate immune cells. Detailed insights into the molecular mechanisms and signaling components involved in immune cell regulation by GPR84 and HCA(3) are still lacking. Here, we report that GPR84-mediated pro-inflammatory signaling depends on coupling to the hematopoietic cell-specific G alpha(15) protein in human macro-phages, while HCA(3) exclusively couples to G alpha(i) protein. We show that activated GPR84 induces G alpha(15)-dependent ERK activation, increases intracellular Ca2+ and IP3 levels as well as ROS production. In contrast, HCA(3) activation shifts macrophage metabolism to a less glycolytic phenotype, which is associated with anti-inflammatory responses. This is supported by an increased release of anti-inflammatory IL-10 and a decreased secretion of pro-inflammatory IL-1 beta. In primary human neutrophils, stimulation with HCA(3) agonists counteracts the GPR84-induced neutrophil activation. Our analyses reveal that 3HDec acts solely through GPR84 but not HCA(3) activation in macrophages. In summary, this study shows that HCA(3) mediates hyporesponsiveness in response to metabolites derived from dietary lactic acid bacteria and uncovers that GPR84, which is already targeted in clinical trials, promotes pro-inflammatory signaling via G alpha(15) protein in macrophages.

Keywords

Hydroxycarboxylic acid receptor 3; GPR84; Macrophages; Neutrophils; D-phenyllactic acid; Lactic acid bacteria

Published in

Pharmacological Research
2022, Volume: 176, article number: 106047
Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

SLU Authors

• Nordström, Anders

  • Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences
    

UKÄ Subject classification

Immunology


Publication identifier

DOI: https://doi.org/10.1016/j.phrs.2021.106047

Permanent link to this page (URI)

https://res.slu.se/id/publ/117184