Hydroxycarboxylic acid receptor 3 and GPR84 – Two metabolite-sensing G protein-coupled receptors with opposing functions in innate immune cells

Peters, Anna; Rabe, Philipp; Liebing, Aenne-Dorothea; Krumbholz, Petra; Nordström, Anders; Jäger, Elisabeth; Kraft, Robert A.; Stäubert, Claudia

doi:10.1016/j.phrs.2021.106047

Cited by 16 publications

(25 citation statements)

References 37 publications

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“…This is the first indication that GPR84 is involved in the development of endotoxin tolerance. Activation of the GPR84 receptor with 6-OAU increases the expression of p-ERK under inflammatory conditions [ 61 , 62 ]. Therefore, in this study, tolerance-like BV2 microglia were treated with 6-OAU prior to secondary stimulation.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Preconditioning Restricts Microglial Overactivation and Alleviates Inflammation-Induced Depressive-like Behavior in Mice

Kan

Tang

et al. 2023

Brain Sciences

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Overactive microglia and severe neuroinflammation play crucial roles in the development of major depressive disorder. Preconditioning with lipopolysaccharide (LPS) provides protection against severe neuroinflammation. However, administering high doses of LPS to mice triggers depressive symptoms. Therefore, the optimal dose of LPS preconditioning needs to be determined by further experiments. LPS preconditioning is an effective agent in anti-inflammation and neuroprotection, but the mechanism by which LPS preconditioning acts in depression remain unclear. This study finds that the anti-inflammation mechanism of low-dose LPS preconditioning is mainly dependent on G-protein-coupled receptor 84 (GPR84). We use low-dose LPS for preconditioning and re-challenged mice or BV2 microglia with high-dose LPS. In addition, RNA-seq is used to explore underlying changes with LPS preconditioning. Low-dose LPS preconditioning reduces the expression of pro-inflammatory mediators and inhibits microglial activation, as well as suppresses the depressive-like behavior when the mice are re-challenged with high-dose LPS. Further investigation reveals that the tolerance-like response in microglia is dependent on the GPR84. Here, we show that low-dose LPS preconditioning can exert anti-inflammation effects and alleviates inflammation-induced depressive-like behavior in mice. As a potential therapeutic target for depression, LPS preconditioning needs to be given further attention regarding its effectiveness and safety.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Preconditioning Restricts Microglial Overactivation and Alleviates Inflammation-Induced Depressive-like Behavior in Mice

Kan

Tang

et al. 2023

Brain Sciences

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“…G protein-coupled receptor 84 (GPR84) is a receptor for medium-chain free fatty acids with carbon chain lengths of C9 to C14 ( 54 ). It is mainly expressed by monocytes, macrophages, and neutrophils and promotes inflammatory responses by activating ERK and elevating levels of intracellular Ca 2+ and IP ( 55 ). Inflammatory colon tissue from patients who suffered from ulcerative colitis is filled with large numbers of GPR84-positive macrophages, whose involvement in the inflammatory response may depend on the activation of NLRP3 inflammasome ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

Novel macrophage-related gene prognostic index for glioblastoma associated with M2 macrophages and T cell dysfunction

Liu

Wang

et al. 2022

Front. Immunol.

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This study aims to construct a Macrophage-Related Gene Prognostic Index (MRGPI) for glioblastoma (GBM) and explore the underlying molecular, metabolic, and immunological features. Based on the GBM dataset from The Cancer Genome Atlas (n = 156), 13 macrophage-related hub genes were identified by weighted gene co-expression network (WGCNA) analysis. 5 prognostic genes screened by Kaplan-Meire (K-M) analysis and Cox regression model were used to construct the MRGPI, including GPR84, NCF2, HK3, LILRB2, and CCL18. Multivariate Cox regression analysis found that the MRGPI was an independent risk factor (HR = 2.81, CI95: 1.13-6.98, p = 0.026), leading to an unfavorable outcome for the MRGPI-high group, which was further validated by 4 validation GBM cohorts (n = 728). Thereafter, the molecular, metabolic, and immune features and the clinical implications of the MRGPI-based groups were comprehensively characterized. Gene set enrichment analysis (GSEA) found that immune-related pathways, including inflammatory and adaptive immune response, and activated eicosanoid metabolic pathways were enriched in the MRGPI-high group. Besides, genes constituting the MRGPI was primarily expressed by monocytes and macrophages at single-cell scope and was associated with the alternative activation of macrophages. Moreover, correlation analysis and receiver operating characteristic (ROC) curves revealed the relevance between the MRGPI with the expression of immune checkpoints and T cell dysfunction. Thus, the responsiveness of samples in the MRGPI-high group to immune checkpoint inhibitors (ICI) was detected by algorithms, including Tumor Immune Dysfunction and Exclusion (TIDE) and Submap. In contrast, the MRGPI-low group had favorable outcome, was less immune active and insensitive to ICI. Together, we have developed a promising biomarker to classify the prognosis, metabolic and immune features for GBM, and provide references for facilitating the personalized application of ICI in GBM.

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“…GPR84 is a rhodopsin-like G protein-coupled receptor (GPCR) discovered 20 years ago that is highly expressed in various types of innate immune cells (neutrophils, monocytes, and macrophages) ( Wittenberger et al., 2001 ; Yousefi et al., 2001 ). We recently demonstrated that this Gα i -coupled receptor additionally recruits Gα 15 proteins in macrophages and neutrophils ( Peters et al., 2022 ). Many studies show that GPR84 expression is increased under pro-inflammatory conditions, including bacterial and viral infections (reviewed in ( Luscombe et al., 2020 ; Marsango et al., 2020 ; Wojciechowicz and Ma’ayan, 2020 )).…”

Section: Introductionmentioning

confidence: 99%

“…Many studies show that GPR84 expression is increased under pro-inflammatory conditions, including bacterial and viral infections (reviewed in ( Luscombe et al., 2020 ; Marsango et al., 2020 ; Wojciechowicz and Ma’ayan, 2020 )). Activation of GPR84 by medium-chain fatty acids (MCFAs, 9–12 carbons) ( Wang et al., 2006 ) and their respective 3-hydroxy derivatives (3-OH-MCFAs) ( Suzuki et al., 2013 ) results in responses like chemotaxis, phagocytosis, and production of reactive oxygen species ( Recio et al., 2018 ; Lucy et al., 2019 ; Peters et al., 2022 ). MCFAs may originate from dietary sources, whereas 3-OH-MCFAs are elevated during ketosis, but are also present in lipopolysaccharides (LPS), which are outer cell-membrane components of gram-negative bacteria ( Szponar et al., 2003 ; Leker et al., 2017 ; Kutschera et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…MCFAs may originate from dietary sources, whereas 3-OH-MCFAs are elevated during ketosis, but are also present in lipopolysaccharides (LPS), which are outer cell-membrane components of gram-negative bacteria ( Szponar et al., 2003 ; Leker et al., 2017 ; Kutschera et al., 2019 ). We recently provided direct evidence for the gram-negative bacteria-derived origin of 3-OH-MCFAs ( Peters et al., 2022 ). Besides its role in immune response, several other functions have been reported for GPR84, including regulation of mitochondrial metabolism in skeletal muscle and modulation of fibrotic disease progression ( Gagnon et al., 2018 ; Montgomery et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Evolutionary analyses reveal immune cell receptor GPR84 as a conserved receptor for bacteria-derived molecules

Schulze¹,

Kleinau²,

Krakowsky³

et al. 2022

iScience

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Hydroxycarboxylic acid receptor 3 and GPR84 – Two metabolite-sensing G protein-coupled receptors with opposing functions in innate immune cells

Cited by 16 publications

References 37 publications

Lipopolysaccharide Preconditioning Restricts Microglial Overactivation and Alleviates Inflammation-Induced Depressive-like Behavior in Mice

Lipopolysaccharide Preconditioning Restricts Microglial Overactivation and Alleviates Inflammation-Induced Depressive-like Behavior in Mice

Novel macrophage-related gene prognostic index for glioblastoma associated with M2 macrophages and T cell dysfunction

Evolutionary analyses reveal immune cell receptor GPR84 as a conserved receptor for bacteria-derived molecules

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