EP2 Receptor Signaling Pathways Regulate Classical Activation of Microglia

Quan, Yi; Jiang, Jianxiong; Dingledine, Raymond

doi:10.1074/jbc.m113.455816

Cited by 92 publications

(107 citation statements)

References 59 publications

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“…8 In contrast, EP2 receptor signaling protects cultured neurons under various conditions through the cAMP/PKA or cAMP/Epac pathway [9][10][11][12] and regulates microglial activation and function in vitro. [13][14][15][16] These findings reflect cell-specific differences in EP2 signaling. In vivo work has shown that the EP2 receptor has beneficial effects in models of ischemic stroke 12,17,18 but detrimental effects in models of Alzheimer's disease, 19,20 Parkinson's disease, 21 and amyotrophic lateral sclerosis.…”

Section: Introductionmentioning

confidence: 87%

“…12,41 Neuronal EP2 signaling has been shown to be protective in in vitro and in vivo models of cerebral ischemia. 11,16,17 Interestingly, in vitro studies have shown that activation of the EP2 receptor also regulates microglial activation and function, [13][14][15][16] which implies a detrimental role in chronic neuropathologic conditions such as Alzheimer's disease, 19,20 Parkinson's disease, 21 and amyotrophic lateral sclerosis. 22 In mice that underwent collagenase-induced ICH, EP2 receptors were expressed primarily in striatal neurons.…”

Section: Discussionmentioning

confidence: 99%

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Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

Han

et al. 2016

J Cereb Blood Flow Metab

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Inflammatory responses mediated by prostaglandins such as PGE 2 may contribute to secondary brain injury after intracerebral hemorrhage (ICH). However, the cell-specific signaling by PGE 2 receptor EP2 differs depending on whether the neuropathic insult is acute or chronic. Using genetic and pharmacologic approaches, we investigated the role of EP2 receptor in two mouse models of ICH induced by intrastriatal injection of collagenase or autologous arterial whole blood. We used middle-aged male mice to enhance the clinical relevance of the study. EP2 receptor was expressed in neurons but not in astrocytes or microglia after collagenase-induced ICH. Brain injury after collagenase-induced ICH was associated with enhanced cellular and molecular inflammatory responses, oxidative stress, and matrix metalloproteinase (MMP)-2/9 activity. EP2 receptor deletion exacerbated brain injury, brain swelling/edema, neuronal death, and neurobehavioral deficits, whereas EP2 receptor activation by the highly selective agonist AE1-259-01 reversed these outcomes. EP2 receptor deletion also exacerbated brain edema and neurologic deficits in the blood ICH model. These findings support the premise that neuronal EP2 receptor activation by PGE 2 protects brain against ICH injury in middle-aged mice through its anti-inflammatory and anti-oxidant effects and anti-MMP-2/9 activity. PGE 2 /EP2 signaling warrants further investigation for potential use in ICH treatment.

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Section: Introductionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

Han

et al. 2016

J Cereb Blood Flow Metab

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“…One possibility is that neuron-released prostaglandin E 2 , a product of cyclooxygenase-2 (COX-2), induces microglial CCL2 expression via EP2 receptors. Indeed, genetic removal of neuronal COX-2 or EP2 antagonism can mitigate the induction of CCL2 mRNA in the brain (6,8,9) or in purified microglia (57). Another possibility is that neuronal ATP release increases CCL2 in microglia via P2X7 receptors (58).…”

Section: Discussionmentioning

confidence: 99%

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Varvel

Neher

Bosch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

288

291

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The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs. brain-infiltrating monocytes. Chemokine receptor 2 (CCR2 + ) monocytes invade the hippocampus between 1 and 3 d after SE. In contrast, only an occasional CD3 + T lymphocyte was encountered 3 d after SE. The initial cellular sources of the chemokine CCL2, a ligand for CCR2, included perivascular macrophages and microglia. The induction of the proinflammatory cytokine IL-1β was greater in FACS-isolated microglia than in brain-invading monocytes. However, Ccr2 knockout mice displayed greatly reduced monocyte recruitment into brain and reduced levels of the proinflammatory cytokine IL-1β in hippocampus after SE, which was explained by higher expression of the cytokine in circulating and brain monocytes in wild-type mice. Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage. Our findings identify brain-infiltrating monocytes as a myeloid-cell subclass that contributes to neuroinflammation and morbidity after SE. Inhibiting brain invasion of CCR2 + monocytes could represent a viable method for alleviating the deleterious consequences of SE. myeloid cell heterogeneity | epileptogenesis | neuroprotection | seizure | microgliosis S tatus epilepticus (SE) is a serious medical emergency that triggers a series of cellular and molecular events that can result in the development of epilepsy, a chronic neurological disorder characterized by a persistently lowered seizure threshold (1). The early consequences of SE in rodents include a robust neuroinflammatory response, selective neuronal degeneration, and transient opening of the blood-brain barrier (BBB), leading to later cognitive decline. Although the neuroinflammatory features of SE in man are less well known, extravasation of albumin into the brain was observed for patients who died in SE (2), elevated cerebrospinal fluid levels of the cytokines IL-6, IL-8, and CXCL10 are typically found in patients with refractory SE compared with patients with other inflammatory neurologic disorders (3), and intense gliosis (both astrocytes and microglia) was observed in the temporal cortex of a patient with new-onset focal seizures that progressed to refractory SE (4). These admittedly sparse clinical findings are consistent with the much more extensive animal literature in demonstrating a florid inflammatory response of the brain to SE (5). We and others have provided evidence in animal models of epilepsy that quenching inflamma...

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“…Con, control group; PGE2, prostaglandin E2; PD-1, programmed cell death-1; CD, cluster of differentiation. EP1 is reported to be associated with intracellular calcium concentration, and promoter analysis of the EP2 and EP4 genes indicated the presence of several consensus sequences associated with inflammatory stimuli, including interleukin-6, nuclear factor-κB and activator protein 2 (29,30). A previous study revealed that EP4 is able to mediate PGE2-induced migration of A549 lung cancer cells (31).…”

Section: Discussionmentioning

confidence: 99%

Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD‑1 in infiltrating CD8+ T cells in patients with lung cancer

et al. 2017

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Abstract. The present study aimed to identify the level of programmed death-1 (PD-1) expression in infiltrating cluster of differentiation (CD)4 + and CD8 + T cells isolated from lung cancer tissues, and investigated whether the level of PD-1 expression may be directly regulated by lung cancer cells via prostaglandin E2 (PGE2)-associated signaling pathways in patients with lung cancer. A total of 75 patients with lung cancer were enrolled in the present study. The percentage of infiltrating CD4 + and CD8 + T cells was determined by flow cytometry. ELISA was performed to evaluate the concentration of PGE2 in lung cancer tissue homogenate. The correlation between PGE2 and PD-1 expression levels in CD8 + T cells was assessed by Spearman's rank correlation test. The expression levels of PD-1 and PGE2 receptors were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The level of PD-1 expression in infiltrating CD8 + T cells was gradually increased as the stage of lung cancer increased. The level of PD-1 expression was also positively associated with the concentration of PGE2 in lung cancer tissues. Furthermore, the level of PD-1 expression was closely associated with the PGE2/EP2 and PGE2/EP4 signaling pathways. The activation of PGE2-associated EP2-and EP4-pathways may positively regulate the level of PD-1 in infiltrating CD8 + T cells, which results in immune tolerance in the lung cancer microenvironment.

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EP2 Receptor Signaling Pathways Regulate Classical Activation of Microglia

Cited by 92 publications

References 59 publications

Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD‑1 in infiltrating CD8+ T cells in patients with lung cancer

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EP2 Receptor Signaling Pathways Regulate Classical Activation of Microglia

Cited by 92 publications

References 59 publications

Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice

Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD‑1 in infiltrating CD8+ T cells in patients with lung cancer

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Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice