Natural biased signaling of hydroxycarboxylic acid receptor 3 and G protein-coupled receptor 84

Abstract

Background: Medium-chain fatty acids and their 3-hydroxy derivatives are metabolites endogenously produced in humans, food-derived or originating from bacteria. They activate G protein-coupled receptors, including GPR84 and HCA 3 , which regulate metabolism and immune functions. Although both receptors are coupled to G i proteins, share at least one agonist and show overlapping tissue expression, GPR84 exerts pro-inflammatory effects whereas HCA 3 is involved in anti-inflammatory responses. Here, we analyzed signaling kinetics of both HCA 3 and GPR84, to unravel signal transduction components that may explain their physiological differences. Methods: To study the signaling kinetics and components involved in signal transduction of both receptors we applied the label-free dynamic mass redistribution technology in combination with classical cAMP, ERK signaling and β-arrestin-2 recruitment assays. For phenotypical analyses, we used spheroid cell culture models. Results: We present strong evidence for a natural biased signaling of structurally highly similar agonists at HCA 3 and GPR84. We show that HCA 3 signaling and trafficking depends on dynamin-2 function. Activation of HCA 3 by 3hydroxyoctanoic acid but not 3-hydroxydecanoic acid leads to β-arrestin-2 recruitment, which is relevant for cellcell adhesion. GPR84 stimulation with 3-hydroxydecanoic acid causes a sustained ERK activation but activation of GPR84 is not followed by β-arrestin-2 recruitment. Conclusions: In summary, our results highlight that biased agonism is a physiological property of HCA 3 and GPR84 with relevance for innate immune functions potentially to differentiate between endogenous, non-pathogenic compounds and compounds originating from e.g. pathogenic bacteria.

20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?

“…In contrast to the more prevalent (R)-hydroxy fatty acids in mammals that we might generate or consume directly, (S)-3-hydroxy fatty acids, including (S)-3-hydroxy capric acid, are components of LPS in Gram-negative bacteria and used as endotoxin markers in clinical samples ( Jenske and Vetter, 2009). Peters et al (2020) hypothesize that GPR84 has a protective role against pathogenic bacteria based on the proinflammatory response to 3-hydroxy capric acid. The characterization of hydroxylated MCFA enantioselectivity has the potential to provide important clues to the function of GPR84 and is the subject of future work.…”

Carboxylic submetabolome-driven signature characterization of COVID-19 asymptomatic infection

“…3-hydroxydecanoic acid is a medium-chain fatty acid, whose sensing receptor GPR84 is a pro-inflammatory receptor [ 30 ]. Peters et al declared that 3-hydroxydecanoic acid can stimulate GPR84 and cause a sustained ERK activation [ 31 ]. The ERK pathway was closely related to the human immunodeficiency regulatory protein, which can enhance the replication and infectivity of viruses such as HIV by regulating T-cell activity [ 32 ].…”

FATTY ACID RECEPTOR GPR84 AND Th1/Th2 BALANCE IN THE EXPERIMENTAL SYSTEM IN VIVO

“…As it turned out, one of the possible explanations may be related to the activation of the hydroxycarboxylic acid receptor 3 (HCA3) by capric acid, which is included in the mixture used in our experiments. Peters A. et al found that the hydroxylated metabolite of this acid (3-OHC10) was able to activate not only GPR84 (with the same efficiency as the native C10), but also the HCA3 receptor [6]. Similar to the mediumchain fatty acid receptor, HCA3 is expressed on immune cells.…”