GPR84 is a member of the metabolic G protein-coupled receptor family, and its expression has been described predominantly in immune cells. GPR84 activation is involved in the inflammatory response, but the mechanisms by which it modulates inflammation have been incompletely described. In this study, we investigated GPR84 expression, activation, and function in macrophages to establish the role of the receptor during the inflammatory response. We observed that GPR84 expression in murine tissues is increased by endotoxemia, hyperglycemia, and hypercholesterolemia. Ex vivo studies revealed that GPR84 mRNA expression is increased by LPS and other pro-inflammatory molecules in different murine and human macrophage populations. Likewise, high glucose concentrations and the presence of oxidized LDL increased GPR84 expression in macrophages. Activation of the GPR84 receptor with a selective agonist, 6-(octylamino) pyrimidine-2,4(1H,3H)-dione (6-n-octylaminouracil, 6-OAU), enhanced the expression of phosphorylated Akt, p-ERK, and p65 nuclear translocation under inflammatory conditions and elevated the expression levels of the inflammatory mediators TNFα, IL-6, IL-12B, CCL2, CCL5, and CXCL1. In addition, GPR84 activation triggered increased bacterial adhesion and phagocytosis in macrophages. The enhanced inflammatory response mediated by 6-OAU was not observed in GPR84−/− cells nor in macrophages treated with a selective GPR84 antagonist. Collectively, our results reveal that GPR84 functions as an enhancer of inflammatory signaling in macrophages once inflammation is established. Therefore, molecules that antagonize the GPR84 receptor may be potential therapeutic tools in inflammatory and metabolic diseases.

GPR84 is an orphan G-protein-coupled receptor that is expressed on immune cells and implicated in several inflammatory diseases. The validation of GPR84 as a therapeutic target is hindered by the narrow range of available chemical tools and consequent poor understanding of GPR84 pathophysiology. Here we describe the discovery and characterization of DL-175, a potent, selective, and structurally novel GPR84 agonist and the first to display significantly biased signaling across GPR84-overexpressing cells, primary murine macrophages, and human U937 cells. By comparing DL-175 with reported GPR84 ligands, we show for the first time that biased GPR84 agonists have markedly different abilities to induce chemotaxis in human myeloid cells, while causing similar levels of phagocytosis enhancement. This work demonstrates that biased agonism at GPR84 enables the selective activation of functional responses in immune cells and delivers a high-quality chemical probe for further investigation.

We identified TREM-1 as a major upstream proatherogenic receptor. We propose that TREM-1 activation orchestrates monocyte/macrophage proinflammatory responses and foam cell formation through coordinated and combined activation of CD36 and TLR4. Blockade of TREM-1 signaling may constitute an attractive novel and double-hit approach for the treatment of atherosclerosis.

Background and Purpose There are no medications currently available to treat metabolic inflammation. Bruton's tyrosine kinase (BTK) is highly expressed in monocytes and macrophages and regulates NF‐κB and NLRP3 inflammasome activity; both propagate metabolic inflammation in diet‐induced obesity. Experimental Approach Using an in vivo model of chronic inflammation, high‐fat diet (HFD) feeding, in male C57BL/6J mice and in vitro assays in primary murine and human macrophages, we investigated if ibrutinib, an FDA approved BTK inhibitor, may represent a novel anti‐inflammatory medication to treat metabolic inflammation. Key Results HFD‐feeding was associated with increased BTK expression and activation, which was significantly correlated with monocyte/macrophage accumulation in the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD‐fed mice inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD‐fed mice decreased the activation of NF‐κB and the NLRP3 inflammasome. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS‐1/Akt/GSK‐3β pathway, protecting mice against the development of hepatosteatosis and proteinuria. We show that BTK regulates NF‐κB and the NLRP3 inflammasome specifically in primary murine and human macrophages, the in vivo cellular target of ibrutinib. Conclusion and Implications We provide “proof of concept” evidence that BTK is a novel therapeutic target for the treatment of diet‐induced metabolic inflammation and ibrutinib may be a candidate for drug repurposing as an anti‐inflammatory agent for the treatment of metabolic inflammation in T2D and microvascular disease.

EGFR blockade induced T cell anergy in vitro and in vivo and reduced atherosclerosis development. Targeting EGFR may be a novel strategy to combat atherosclerosis.

Our findings, using state-of-the-art mouse models, demonstrate that NK cells have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis, but may play a role when an additional systemic NK-cell overactivation occurs.

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Gene deletion of in myeloid cells limits IL-6 and TNF-α production, lipid uptake, and consecutively reduces atherosclerosis development.