OGR1/GPR68 Modulates the Severity of Experimental Autoimmune Encephalomyelitis and Regulates Nitric Oxide Production by Macrophages

D'Souza, Cheryl; Zhao, Fei; Li, Xujian; Xu, Yan; Dunn, Shannon; Zhang, Li

doi:10.1371/journal.pone.0148439

Cited by 16 publications

(13 citation statements)

References 50 publications

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“…Examples of a direct involvement either in autoimmunity, or MS susceptibility and pathogenesis, include GFI1 20 , 21 , ZMIZ1 2 , 22 and NFE2L2 23 . Moreover, CNTNAP2 24 and DDR1 25 are involved in demyelination/remyelination processes and could be indirectly linked to MS, while AHRR 26 , ITGB7 27 , PPIF 28 and GPR68 29 have been studied in the context of EAE. Ultimately, 12 out of the 58 reported DMPs lie within an LD block containing at least one SNP considered as an MS risk according to the GWAS catalog.…”

Section: Resultsmentioning

confidence: 99%

Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship

Marabita

Almgren

Sjöholm

et al. 2017

Sci Rep

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Cigarette smoking is an established environmental risk factor for Multiple Sclerosis (MS), a chronic inflammatory and neurodegenerative disease, although a mechanistic basis remains largely unknown. We aimed at investigating how smoking affects blood DNA methylation in MS patients, by assaying genome-wide DNA methylation and comparing smokers, former smokers and never smokers in two Swedish cohorts, differing for known MS risk factors. Smoking affects DNA methylation genome-wide significantly, an exposure-response relationship exists and the time since smoking cessation affects methylation levels. The results also show that the changes were larger in the cohort bearing the major genetic risk factors for MS (female sex and HLA risk haplotypes). Furthermore, CpG sites mapping to genes with known genetic or functional role in the disease are differentially methylated by smoking. Modeling of the methylation levels for a CpG site in the AHRR gene indicates that MS modifies the effect of smoking on methylation changes, by significantly interacting with the effect of smoking load. Alongside, we report that the gene expression of AHRR increased in MS patients after smoking. Our results suggest that epigenetic modifications may reveal the link between a modifiable risk factor and the pathogenetic mechanisms.

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Section: Resultsmentioning

confidence: 99%

Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship

Marabita

Almgren

Sjöholm

et al. 2017

Sci Rep

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“…It has been suggested that the expression of Gpr68 in myeloid-derived cells is required for prostate cancer cell-induced immunosuppression (Yan et al, 2014). GPR68 mice also have impaired T cell responses associated with a reduced frequency and number of dendritic cells (DCs), higher production of nitric oxide by macrophages, and defect in DCs migration to draining lymph nodes (Aoki et al, 2013; D’Souza et al, 2016). There’s also evidence suggesting that GPR68 could be involved in recall of fear conditioning in mice (Huang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

GPR68 Senses Flow and Is Essential for Vascular Physiology

Mathur

Vessières

et al. 2018

Cell

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248

219

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Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.

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“…GPR68 (OGR1) is a proton-sensing receptor that can detect decreases in extracellular pH during inflammation. It is expressed in macrophages (184), dendritic cells (187), T cells (188), and neutrophils (186) and has a pro-inflammatory function in colitis (189), asthma through activation of dendritic cells (187), and in murine experimental autoimmune encephalomyelitis that regulates T cell responses during autoimmunity (190). This receptor has been described to be able to couple Gaq/11 and Gas and trigger increased intracellular calcium and cAMP (Table 1) (191,192).…”

Section: Gaq/ 11 and Gasmentioning

confidence: 99%

Role of Lactate in Inflammatory Processes: Friend or Foe

et al. 2022

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During an inflammatory process, shift in the cellular metabolism associated with an increase in extracellular acidification are well-known features. This pH drop in the inflamed tissue is largely attributed to the presence of lactate by an increase in glycolysis. In recent years, evidence has accumulated describing the role of lactate in inflammatory processes; however, there are differences as to whether lactate can currently be considered a pro- or anti-inflammatory mediator. Herein, we review these recent advances on the pleiotropic effects of lactate on the inflammatory process. Taken together, the evidence suggests that lactate could exert differential effects depending on the metabolic status, cell type in which the effects of lactate are studied, and the pathological process analyzed. Additionally, various targets, including post-translational modifications, G-protein coupled receptor and transcription factor activation such as NF-κB and HIF-1, allow lactate to modulate signaling pathways that control the expression of cytokines, chemokines, adhesion molecules, and several enzymes associated with immune response and metabolism. Altogether, this would explain its varied effects on inflammatory processes beyond its well-known role as a waste product of metabolism.

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OGR1/GPR68 Modulates the Severity of Experimental Autoimmune Encephalomyelitis and Regulates Nitric Oxide Production by Macrophages

Cited by 16 publications

References 50 publications

Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship

Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship

GPR68 Senses Flow and Is Essential for Vascular Physiology

Role of Lactate in Inflammatory Processes: Friend or Foe

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