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  • Another important question is what ligand

    2021-10-15

    Another important question is what ligand(s) bind to GPR84 in vivo? Previous studies have identified medium-chain FFAs of 9 to 14 carbons in length and two other organic molecules (6-n-octylaminouracil and 3,3′-diindolylmethane) as agonists of GPR84 in vitro (Wang et al., 2006, Suzuki et al., 2013). The hydroxylated forms of these FFAs were found to be more effective than the nonhydroxylated ones (Suzuki et al., 2013). Derived from the diet or the hydrolysis of triglycerides, FFAs serve as an energy source. They can also be hydroxylated and incorporated into sphingolipids (Hama, 2010). The latter are especially abundant in the nervous system, in which they represent a major component of myelin (Dupree and Pomicter, 2010). Sphingolipids play not only a structural role, but also contribute to cell signaling and adhesion (Hannun and Obeid, 2008). As lipid dysregulation is an important feature of AD (Benilova et al., 2012, Walter and van Echten-Deckert, 2013), it is tempting to speculate that FFA metabolites, generated in response to β-amyloid, could act as danger signals. GPR84 could play a central role in the ability of microglia to perceive these signals and trigger an appropriate response (e.g., chemotaxis, as supported by Suzuki et al., 2013). This is likely as there are many examples of lipid molecules that bind to G-protein-coupled receptors on immune cells, including other fatty acids, arachidonic rp gift card metabolites and lysophospholipids (Kostenis, 2004). Further work will be required to identify the endogenous GPR84 ligands and go beyond speculation. In conclusion, this study: (1) identifies for the first time a pathophysiological role of GPR84; (2) provides an in vivo model in which to search for endogenous GPR84 ligands; and (3) supports the concept that microglia exert a modest, but beneficial effect in AD. Future studies on GPR84 may help to clarify the link between lipid dysregulation and neuroinflammation in AD.
    Conflict of interest
    Acknowledgments This work was supported by grants from the Canadian Institutes for Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada and the Multiple Sclerosis Society of Canada. L.V. and S.L. received Chercheur-Boursier Sénior awards from the Fonds de recherche du Québec – Santé. JAR was supported by a CIHR Strategic Training Program Grant in genomics. L.B. received a Merit Scholarship from the Fonds de recherche du Québec – Nature et technologies. MET was funded by the Banting Research Foundation and the Scottish Rite Charitable Foundation of Canada. We thank Pierrot Tremblay, Julie Pagé and Martin Parent for technical assistance.
    Introduction G-protein coupled receptors (GPCRs) regulate a variety of cellular functions including growth, differentiation, secretion and locomotion [1]. The signaling pathways that link GPCRs to their biological functions are primarily mediated by heterotrimeric G-proteins comprising the α and βγ subunits. The α subunits are further classified into the Gi, Gq and Gs family of proteins. Binding of a ligand to its cognate receptor results in the activation of various signaling pathways that can generally be linked to different biological responses in the cell. A variety of GPCRs are expressed in the immune system, including receptors for chemokines, inflammatory mediators such as leukotrienes and prostaglandins, and neurotransmitters [1]. The chemokine family of receptors has gained a lot of attention in the last decade because of their critical role in modulating the recruitment of various inflammatory cells during an ongoing immune response [2]. In addition, leukotrienes play an important role in regulating vascular permeability for promoting extravasation of inflammatory cells [3]. Thus, these two families of proteins are attractive drug targets for various immune-related diseases. Large-scale data mining approaches have led to the identification of several novel GPCRs that have either a general or tissue-restricted expression pattern. One such receptor of this family GPR84 was recently identified and is encoded by a single exon with an open reading frame of 1191bp [4]. The human and mouse GPR84 genes encode for a protein of 396 amino acids in length with 85% identity [4]. GPR84 was also identified by Yousefi et al. (designated as EX33) using a degenerate primer RT-PCR approach aimed to identify novel chemokine receptors expressed on neutrophils [5]. It was reported that the expression of EX33 was detected in neutrophils, eosinophils and phorbol ester activated peripheral blood mononuclear cells [5]. The nature of the ligand that binds to GPR84/EX33 has not been reported yet. In this study, GPR84-deficient mice were generated to analyze the biological function of this receptor in immune cells. Interestingly, these studies reveal a novel role for GPR84 in regulating early IL-4 gene expression in activated T cells.