Molecular mechanisms of microglial activation

Microglia take on an altered morphology during chronic opioid treatment. This morphological change is broadly used to identify the activated microglial state associated with opioid side effects, including tolerance and opioid-induced hyperalgesia (OIH). Following chronic opioid treatment and peripheral nerve injury (PNI) microglia in the spinal cord display similar morphological responses. Consistent with this observation, functional studies have suggested that microglia activated by PNI or opioids engage common molecular mechanisms to induce hypersensitivity. Here we conducted deep RNA sequencing of acutely isolated spinal cord microglia from male mice to comprehensively interrogate transcriptional states and mechanistic commonality between multiple OIH and PNI models. Following PNI, we identify a common early proliferative transcriptional event across models that precedes the upregulation of histological markers of activation, followed by a delayed and injury-specific transcriptional response. Strikingly, we found no such transcriptional responses associated with opioid-induced microglial activation, consistent with histological data indicating that microglia number remain stable during morphine treatment. Collectively, these results reveal the diversity of pain-associated microglial transcriptomes and point towards the targeting of distinct insult-specific microglial responses to treat OIH, PNI, or other CNS pathologies.

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A specific RIP3+ subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2023290118 ◽

2021 ◽

Vol 118 (11) ◽

pp. e2023290118

Author(s):

Chang He ◽

Yan Liu ◽

Zijing Huang ◽

Ziqi Yang ◽

Tian Zhou ◽

...

Keyword(s):

Microglial Activation ◽

Visual Loss ◽

Molecular Mechanisms ◽

Retinal Neovascularization ◽

Loss Of Function ◽

Severe Visual Loss ◽

Single Cell Rna Sequencing ◽

Retinal Angiogenesis ◽

Signaling Components ◽

Specific Deletion

Retinal neovascularization is a leading cause of severe visual loss in humans, and molecular mechanisms of microglial activation-driven angiogenesis remain unknown. Using single-cell RNA sequencing, we identified a subpopulation of microglia named sMG2, which highly expressed necroptosis-related genes Rip3 and Mlkl. Genetic and pharmacological loss of function demonstrated that hypoxia-induced microglial activation committed to necroptosis through the RIP1/RIP3-mediated pathway. Specific deletion of Rip3 gene in microglia markedly decreased retinal neovascularization. Furthermore, hypoxia induced explosive release of abundant FGF2 in microglia through RIP3-mediated necroptosis. Importantly, blocking signaling components of the microglia necropotosis–FGF2 axis largely ablated retinal angiogenesis and combination therapy with simultaneously blocking VEGF produced synergistic antiangiogenic effects. Together, our data demonstrate that targeting the microglia necroptosis axis is an antiangiogenesis therapy for retinal neovascular diseases.

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URMC-099 Prophylaxis Repairs Hippocampal Vascular Damage in an Orthopedic Model of Delirium Superimposed on Dementia

10.1101/2021.10.04.463042 ◽

2021 ◽

Author(s):

Patrick Miller-Rhodes ◽

Herman Li ◽

Ravikanth Velagapudi ◽

Niccolo Terrando ◽

Harris A Gelbard

Keyword(s):

Cognitive Deficits ◽

Microglial Activation ◽

Molecular Mechanisms ◽

Amyloid Β ◽

Endothelial Activation ◽

Surgical Trauma ◽

Data Link ◽

Synapse Loss ◽

The Brain ◽

Delirium Superimposed On Dementia

Systemic perturbations can drive a neuroimmune cascade after surgical trauma, including affecting the blood-brain barrier (BBB), activating microglia, and contributing to cognitive deficits such as delirium. Delirium superimposed on dementia (DSD) is a particularly debilitating complication that renders the brain further vulnerable to neuroinflammation and neurodegeneration, albeit these molecular mechanisms remain poorly understood. Here we have used an orthopedic model of tibial fracture/fixation in APPSwDI/mNos2-/- AD (CVN-AD) mice to investigate relevant pathogenetic mechanisms underlying DSD. We conducted the present study in 6 months-old CVN-AD mice, an age at which we speculated amyloid-β pathology had not saturated BBB and neuroimmune functioning. We found that URMC-099, our brain-penetrant anti-inflammatory neuroprotective drug, prevented inflammatory endothelial activation, synapse loss, and microglial activation in our DSD model. Taken together, our data link post-surgical endothelial activation, microglial MafB immunoreactivity, and synapse loss as key substrates for DSD, all of which can be reversed by URMC-099.

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Effects ofFructus mumeExtract on MAPK and NF-κB Signaling and the Resultant Improvement in the Cognitive Deficits Induced by Chronic Cerebral Hypoperfusion

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/450838 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 7

Author(s):

Won Kyung Jeon ◽

Jinhua Ma ◽

Bo-Ryoung Choi ◽

Seol-Heui Han ◽

Qinghao Jin ◽

...

Keyword(s):

Microglial Activation ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Artery Occlusion ◽

Chronic Cerebral Hypoperfusion ◽

Mitogen Activated Protein Kinase ◽

Daily Administration ◽

Cerebral Hypoperfusion ◽

Memory Impairments ◽

The Status

Fructus mume(F. mume) has been used as a medicinal food in Japan and has been reported to have anti-inflammatory effects in inflammatory bowel disease and macrophage-mediated inflammation. We investigated the effects ofF. mumeextracts on cognitive dysfunction in rats with chronic cerebral hypoperfusion and the molecular mechanisms underlying these effects. Chronic cerebral hypoperfusion was induced in male Wister rats by bilateral common artery occlusion (BCCAo). Daily administration ofF. mumeextracts was started on day 20 after post-BCCAo and continued for 40 days. The status of hippocampus-dependent memory was evaluated in control rats, rats with chronic cerebral hypoperfusion, and rats with chronic cerebral hypoperfusion that were administeredF. mume. The levels of microglial activation were measured in the hippocampus and the fimbria of hippocampus, and expression levels of hippocampal mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were examined. Rats that received chronic cerebral hypoperfusion showed spatial memory impairments relative to the control rats; these impairments were reduced by daily administration ofF. mume. Administration ofF. mumemitigated the microglial activation and alterations of hippocampal MAPK and NF-κB signaling in the rats with chronic cerebral hypoperfusion. These results indicate thatF. mumemay possess therapeutic potential for the prevention of vascular dementia via inhibition of inflammatory processes.

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JAM-A functions as a female microglial tumor suppressor in glioblastoma

10.1101/761445 ◽

2019 ◽

Author(s):

Soumya M. Turaga ◽

Daniel J. Silver ◽

Defne Bayik ◽

Evi Paouri ◽

Sen Peng ◽

...

Keyword(s):

Sex Differences ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Microglial Activation ◽

Molecular Mechanisms ◽

Gene Activation ◽

Epidemiological Studies ◽

Resistance Mechanisms ◽

Molecular Heterogeneity ◽

Biological Sex

AbstractGlioblastoma (GBM) remains refractory to treatment. In addition to its cellular and molecular heterogeneity, epidemiological studies indicate the presence of additional complexity associated with biological sex. GBM is more prevalent and aggressive in male compared to female patients, suggesting the existence of sex-specific growth, invasion, and therapeutic resistance mechanisms. While sex-specific molecular mechanisms have been reported at a tumor cell-intrinsic level, sex-specific differences in the tumor microenvironment have not been investigated. Using transgenic mouse models, we demonstrate that deficiency of junctional adhesion molecule-A (JAM-A) in female mice enhances microglia activation, GBM cell proliferation, and tumor growth. Mechanistically, JAM-A suppresses anti-inflammatory/pro-tumorigenic gene activation via interferon-activated gene 202b (Ifi202b) and found in inflammatory zone (Fizz1) in female microglia. Our findings suggest that cell adhesion mechanisms function to suppress pathogenic microglial activation in the female tumor microenvironment, which highlights an emerging role for sex differences in the GBM microenvironment and suggests that sex differences extend beyond previously reported tumor cell intrinsic differences.SummaryTuraga et al. demonstrate that female microglia drive a more aggressive glioblastoma phenotype in the context of JAM-A deficiency. These findings highlight a sex-specific role for JAM-A and represent the first evidence of sexual dimorphism in the glioblastoma microenvironment.

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Loss of CREST leads to neuroinflammatory responses and ALS-like motor defects in mice

10.1101/260133 ◽

2018 ◽

Author(s):

Cheng Cheng ◽

Kan Yang ◽

Xinwei Wu ◽

Yuefang Zhang ◽

Shifang Shan ◽

...

Keyword(s):

Motor Neurons ◽

Microglial Activation ◽

Molecular Mechanisms ◽

Motor Coordination ◽

Inflammatory Responses ◽

Late Onset ◽

Critical Role ◽

Histone Deacetylation ◽

Loss Of Function ◽

Sporadic Als

SUMMARYAmyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease with fast progression. Mutations of the CREST gene (also known as SS18L1) are identified in sporadic ALS patients. Whether CREST mutations may lead to ALS remained largely unclear. In this study, we showed that the ALS-related CREST-Q388X mutation exhibited loss-of-function effects. Importantly, we found that microglial activation were prevalent in CREST haploinsufficieny mice and the Q394X mice mimicking the human CREST Q388X mutation. Furthermore, we showed that both CREST haploinsufficieny and the Q394X mice displayed deficits in motor coordination. Finally, we identified the critical role of CREST-BRG1 complex in repressing the expression of immune-related cytokines including Ccl2 and Cxcl10 in neurons, via histone deacetylation, providing the molecular mechanisms underlying inflammatory responses lack of CREST. These findings indicate that elevated inflammatory responses in a subset of ALS may be caused by neuron-derived factors, suggesting potential therapeutic methods through inflammation pathways.In BriefCheng et al. discovered that neuronal loss of CREST reduces the protein level of FUS, de-represses the transcriptional inhibition of chemokine genes which in turn causes microglial activation and proinflammation, and ultimately leads to axonal degeneration of motor neurons and impairment of locomotion.

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CX3CL1 action on microglia protects from diet-induced obesity by restoring POMC neuronal excitability and melanocortin system activity impaired by high-fat diet feeding

10.1101/2021.11.08.467521 ◽

2021 ◽

Author(s):

Jineta Banerjee ◽

Mauricio D. Dorfman ◽

Rachael Fasnacht ◽

John D. Douglass ◽

Alice C. Wyse-Jackson ◽

...

Keyword(s):

High Fat Diet ◽

Microglial Activation ◽

Molecular Mechanisms ◽

Melanocortin Receptor ◽

High Fat ◽

Diet Induced Obesity ◽

Leptin Sensitivity ◽

Neuron Excitability ◽

Melanocortin Signaling

Objective: Diet-induced obesity (DIO) is associated with hypothalamic microglial activation and dysfunction of the melanocortin pathway, but the molecular mechanisms linking the two remain unclear. Previous studies have hypothesized that microglial inflammatory signaling is linked with impaired pro-opiomelanocortin (POMC) neuron function, but this mechanism has never been directly tested in vivo. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling in the brain to protect against DIO. Methods: We performed metabolic analyses in mice with targeted viral overexpression of CX3CL1 in the hypothalamus exposed to high fat diet (HFD). Electrophysiologic recording in hypothalamic slices from POMC-MAPT-GFP mice was used to determine the effects of HFD feeding and microglial silencing via minocycline or CX3CL1 on GFP-labeled POMC neurons. Finally, mice with hypothalamic overexpression of CX3CL1 received central treatment with the melanocortin receptor antagonist SHU-9119 to determine whether melanocortin signaling is required for the metabolic benefits of CX3CL1. Results: We found that targeted expression of both soluble and membrane-bound forms of CX3CL1 in the mediobasal hypothalamus potently reduced weight gain and increased leptin sensitivity in animals exposed to high fat diet. The protective effect of CX3CL1 rescued diet-induced changes in POMC neuron excitability and required intact melanocortin receptor signaling in vivo. Conclusion: Our results provide the first evidence that HFD-induced POMC neuron dysfunction involves microglial activation. Furthermore, our study suggests that the anti-obesity action of CX3CL1 is mediated through the restoration of POMC neuron excitability and melanocortin signaling.

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High doses of minocycline may induce delayed activation of microglia in aged rats and thus cannot prevent postoperative cognitive dysfunction

Journal of International Medical Research ◽

10.1177/0300060517754032 ◽

2018 ◽

Vol 46 (4) ◽

pp. 1404-1413 ◽

Cited By ~ 5

Author(s):

Wenyao Li ◽

Qing Chai ◽

Hongwei Zhang ◽

Jing Ma ◽

Chengfen Xu ◽

...

Keyword(s):

Abdominal Surgery ◽

Cognitive Dysfunction ◽

Microglial Activation ◽

Molecular Mechanisms ◽

Postoperative Cognitive Dysfunction ◽

Morris Water Maze Test ◽

High Morbidity ◽

Mrna Levels ◽

Aged Rats ◽

High Doses

Objective Postoperative cognitive dysfunction (POCD) is common after surgery in elderly patients and is associated with high morbidity. The molecular mechanisms responsible for POCD are unknown. Minocycline, an inhibitor of microglial activation, may be useful in treating and preventing POCD. We explored whether minocycline can inhibit microglial activation and prevent POCD in aged rats as a surgery model. Methods Rats aged 18 to 20 months were randomly allocated to the following groups: naïve, abdominal surgery alone, or minocycline injection before abdominal surgery. Hippocampal cytokine mRNA levels were measured at 3 hours, 1 day, 3 days, and 7 days after surgery, and microglial activation was measured at 3 hours and 7 days after surgery. Memory was assessed using the Morris water maze test. Results Surgery resulted in severe cognitive impairment in aged rats and induced a significant neuroinflammatory response and microglial activation. The use of minocycline can prevent microglial activation after surgery, but delayed microglial activation may occur. The use of minocycline may further impair memory after surgery. Conclusion Minocycline can restrain microglial activation and restrict the inflammatory response in the hippocampus early after surgery, but it may induce delayed microglial activation and cannot prevent POCD in aged rats.

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Common cellular and molecular mechanisms and interactions between microglial activation and aberrant neuroplasticity in depression

Neuropharmacology ◽

10.1016/j.neuropharm.2020.108336 ◽

2020 ◽

Vol 181 ◽

pp. 108336

Author(s):

Xiaoyun Guo ◽

Yanxia Rao ◽

Ruizhi Mao ◽

Lvchun Cui ◽

Yiru Fang

Keyword(s):

Microglial Activation ◽

Molecular Mechanisms

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Atractylodis Rhizoma Alba Attenuates Neuroinflammation in BV2 Microglia upon LPS Stimulation by Inducing HO-1 Activity and Inhibiting NF-κB and MAPK

International Journal of Molecular Sciences ◽

10.3390/ijms20164015 ◽

2019 ◽

Vol 20 (16) ◽

pp. 4015 ◽

Cited By ~ 5

Author(s):

Yun Hee Jeong ◽

Wei Li ◽

Younghoon Go ◽

You-Chang Oh

Keyword(s):

Nitric Oxide ◽

High Performance ◽

Microglial Activation ◽

Molecular Mechanisms ◽

Ethanolic Extract ◽

Brain Diseases ◽

Inflammatory Factors ◽

Bv2 Cells ◽

Mitogen Activated Protein ◽

Bv2 Microglia

Microglial activation and the resulting neuroinflammation are associated with a variety of brain diseases, such as Alzheimer’s disease and Parkinson’s disease. Thus, the control of microglial activation is an important factor in the development of drugs that can treat or prevent inflammation-related neurodegenerative disorders. Atractylodis Rhizoma Alba (ARA) has been reported to exhibit antioxidant, gastroprotective, and anti-inflammatory effects. However, the effects of ARA ethanolic extract (ARAE) on microglia-mediated neuroinflammation have not been fully elucidated. In this work, we explored the anti-neuroinflammatory properties and underlying molecular mechanisms of ARAE in lipopolysaccharide (LPS)-stimulated microglial BV2 cells. Our results showed that ARAE significantly attenuates the production of nitric oxide (NO) and inflammatory cytokines induced by LPS. ARAE treatment also inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 without causing cytotoxicity. ARAE markedly attenuated the transcriptional activities of nuclear factor (NF)-κB and mitogen-activated protein kinases (MAPK) phosphorylation, and induced heme oxygenase (HO)-1 expression. High-performance liquid chromatography (HPLC) analysis showed that ARAE contains three main components—atractylenolide I, atractylenolide III, and atractylodin—all compounds that significantly inhibit the production of inflammatory factors. These findings indicate that ARAE may be a potential therapeutic agent for the treatment of inflammation-related neurodegenerative diseases.

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