P2Y12 expression and function in alternatively activated human microglia

Moore, Craig S.; Ase, Ariel R.; Kinsara, Angham; Rao, Vijayaraghava T.S.; Michell‐Robinson, Mackenzie A.; Leong, Soo Yuen; Butovsky, Oleg; Ludwin, Samuel K.; Séguéla, Philippe; Bar‐Or, Amit; Antel, Jack P.

doi:10.1212/nxi.0000000000000080

Cited by 150 publications

(140 citation statements)

References 43 publications

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“…The uptake of double-stranded DNA can induce activation of TLRs. The purinergic receptor P2Y12 is a TGF-β-responsive molecule uniquely expressed on mouse and human microglia and not on perivascular macrophages or blood-derived monocytes (50), and is expressed predominantly in homeostatic-type microglia (87). ADP is the endogenous ligand of P2Y12, and homeostatic microglia have increased ligand-mediated calcium responses, which are blocked by selective P2Y12 antagonism (87).…”

Section: Immune Cells Involved In Neurodegenerationmentioning

confidence: 99%

“…The purinergic receptor P2Y12 is a TGF-β-responsive molecule uniquely expressed on mouse and human microglia and not on perivascular macrophages or blood-derived monocytes (50), and is expressed predominantly in homeostatic-type microglia (87). ADP is the endogenous ligand of P2Y12, and homeostatic microglia have increased ligand-mediated calcium responses, which are blocked by selective P2Y12 antagonism (87). that distinguish resident microglia from peripheral mononuclear cells/macrophages (50-52) include FSRSL, P2Y12, TMEM119, CX3CR1, Siglec-H, and the microRNAs miR-99a, miR-125-5p, and miR-342-3p, which are highly expressed in both mouse and human microglia (50,53).…”

Section: Immune Cells Involved In Neurodegenerationmentioning

confidence: 99%

See 1 more Smart Citation

CNS inflammation and neurodegeneration

Chitnis¹,

Weiner²

2017

Journal of Clinical Investigation

386

240

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Section: Immune Cells Involved In Neurodegenerationmentioning

confidence: 99%

Section: Immune Cells Involved In Neurodegenerationmentioning

confidence: 99%

CNS inflammation and neurodegeneration

Chitnis¹,

Weiner²

2017

Journal of Clinical Investigation

386

240

View full text Add to dashboard Cite

“…Future evaluation of microglial gene expression in post-mortem brains of PD patients who died at different stages of disease may aid investigators to better define microglial phenotypes. It is becoming increasingly clear that in many diseases, microglia largely express complex gene expression signatures (Butovsky et al, 2014; Moore et al, 2015; Pisanu et al, 2014; Tang and Le, 2015), and mixed phenotypes most likely reflect a dynamic state or may be simply due to the presence of a heterogeneous population of microglia during disease. Until human studies can be conducted to evaluate the neuroinflammatory interaction with neurodegeneration and other histopathological hallmarks like Lewy Body formation, conclusions about these relationships will have to be drawn from animal models of the disease.…”

Section: Microglia In Parkinson’s Disease (Pd)mentioning

confidence: 99%

Microglial phenotypes in Parkinson’s disease and animal models of the disease

Joers

Tansey

Mulas

et al. 2017

Progress in Neurobiology

223

160

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Over the last decade the important concept has emerged that microglia, similar to other tissue macrophages, assume different phenotypes and serve several effector functions, generating the theory that activated microglia can be organized by their pro-inflammatory or anti-inflammatory and repairing functions. Importantly, microglia exist in a heterogenous population and their phenotypes are not permanently polarized into two categories; they exist along a continuum where they acquire different profiles based on their local environment. In Parkinson’s disease (PD), neuroinflammation and microglia activation are considered neuropathological hallmarks, however their precise role in relation to disease progression is not clear, yet represent a critical challenge in the search of disease-modifying strategies. This review will critically address current knowledge on the activation states of microglia as well as microglial phenotypes found in PD and in animal models of PD, focusing on the expression of surface molecules as well as pro-inflammatory and anti-inflammatory cytokine production during the disease process. While human studies have reported an elevation of both pro- or anti-inflammatory markers in the serum and CSF of PD patients, animal models have provided insights on dynamic changes of microglia phenotypes in relation to disease progression especially prior to the development of motor deficits. We also review recent evidence of malfunction at multiple steps of NFκB signaling that may have a causal interrelationship with pathological microglia activation in animal models of PD. Finally, we discuss the immune-modifying strategies that have been explored regarding mechanisms of chronic microglial activation.

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“…Tested by double-label immunofluorescence, P2Y12 and GS (a marker of SGCs) were colocalized in the SGCs of the SG. P2Y12 receptor activation in human microglia results in increased release of TNF-α and IL-6 [36], whereas P2Y12 inhibitors reduce the levels of TNF-α and C-reactive protein (CRP) [37]. The elevated GS in the SG in our study suggested that SGCs were activated by the nerve injury stimulation induced by T2DM.…”

Section: Discussionmentioning

confidence: 74%

Effects of Baicalin on Diabetic Cardiac Autonomic Neuropathy Mediated by the P2Y12 Receptor in Rat Stellate Ganglia

Xuan

Wang²,

Guo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chronic diabetic hyperglycemia can damage various of organ systems and cause serious complications. Although diabetic cardiac autonomic neuropathy (DCAN) is the primary cause of death in diabetic patients, its pathogenesis remains to be fully elucidated. Baicalin is a flavonoid extracted from Scutellaria baicalensis root and has antibacterial, diuretic, anti-inflammatory, anti- metamorphotic, and antispasmodic effects. Our study explored the effects of baicalin on enhancing sympathoexcitatory response induced by DCAN via the P2Y12 receptor. Methods: A type 2 diabetes mellitus rat model was induced by a combination of diet and streptozotocin. Serum epinephrine was measured by enzyme-linked immunosorbent assay. Blood pressure and heart rate were measured using the indirect tail-cuff method. Heart rate variability was analyzed using the frequency-domain of electrocardiogram recordings. The expression levels of P2Y12, interleukin-1beta (IL-1β), tumor necrosis factor alpha (TNF-α), and connexin 43 (Cx43) were determined by quantitative real-time reverse transcription-polymerase chain reaction and western blotting. The interaction between baicalin and P2Y12 determined using by molecular docking. Results: Baicalin alleviated elevated blood pressure and heart rate, improved heart rate variability, and decreased the elevated expression levels of P2Y12, IL-1β, TNF-α, and Cx43 in the stellate ganglia of diabetic rats. Baicalin also reduced the elevated concentration of serum epinephrine and the phosphorylation of p38 mitogen-activated protein kinase in diabetic rats. Conclusion: Baicalin decreases sympathetic activity by inhibiting the P2Y12 receptor in stellate ganglia satellite glial cells to maintain the balance between sympathetic and parasympathetic nerves and relieves DCAN in the rat.

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P2Y12 expression and function in alternatively activated human microglia

Cited by 150 publications

References 43 publications

CNS inflammation and neurodegeneration

CNS inflammation and neurodegeneration

Microglial phenotypes in Parkinson’s disease and animal models of the disease

Effects of Baicalin on Diabetic Cardiac Autonomic Neuropathy Mediated by the P2Y12 Receptor in Rat Stellate Ganglia

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