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Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage.

ABSTRACT: Aged microglia display augmented inflammatory activity after neural injury. Although aging is a risk factor for poor outcome after brain insults, the precise impact of aging-related alterations in microglia on neural injury remains poorly understood. Microglia can be eliminated via pharmacological inhibition of the colony-stimulating factor 1 receptor (CSF1R). Upon withdrawal of CSF1R inhibitors, microglia rapidly repopulate the entire brain, leading to replacement of the microglial compartment. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection. We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.

SUBMITTER: Li X

PROVIDER: S-EPMC8748975 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage.

Li Xiuping X Gao Xiaolin X Zhang Wenyan W Liu Mingming M Han Zhaoli Z Li Minshu M Lei Ping P Liu Qiang Q

Cell death & disease 20220110 1

Aged microglia display augmented inflammatory activity after neural injury. Although aging is a risk factor for poor outcome after brain insults, the precise impact of aging-related alterations in microglia on neural injury remains poorly understood. Microglia can be eliminated via pharmacological inhibition of the colony-stimulating factor 1 receptor (CSF1R). Upon withdrawal of CSF1R inhibitors, microglia rapidly repopulate the entire brain, leading to replacement of the microglial compartment. ...[more]

PMID: 35013119

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Project description:Microglial-mediated neuroinflammation is crucial in the pathophysiological mechanisms of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). Mitochondria are central regulators of inflammation, influencing key pathways such as alternative splicing, and play a critical role in cell differentiation and function. Mitochondrial ATP synthase coupling factor 6 (ATP5J) participates in various pathological processes, such as cell proliferation, migration, and inflammation. However, the role of ATP5J in microglial activation and neuroinflammation post-ICH is poorly understood. This study aimed to investigate the effects of ATP5J on microglial activation and subsequent neuroinflammation in ICH and to elucidate the underlying mechanisms. We observed that ATP5J was upregulated in microglia after ICH. AAV9-mediated ATP5J overexpression worsened neurobehavioral deficits, disrupted the blood-brain barrier, and increased brain water content in ICH mice. Conversely, ATP5J knockdown ameliorated these effects. ATP5J overexpression also intensified microglial activation, neuronal apoptosis, and inflammatory responses in surrounding tissues post-ICH. ATP5J impaired microglial dynamics and reduced the proliferation and migration of microglia to injury sites. We used oxyhemoglobin (OxyHb) to stimulate BV2 cells and model ICH in vitro. Further in vitro studies showed that ATP5J overexpression enhanced OxyHb-induced microglial functional transformation. Mechanistically, ATP5J silencing reversed dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1) upregulation in microglia post-OxyHb induction; reduced mitochondrial overdivision, excessive mitochondrial permeability transition pore opening, and reactive oxygen species production; restored normal mitochondrial ridge morphology; and partially restored mitochondrial respiratory electron transport chain activity. ATP5J silencing further alleviated OxyHb-induced mitochondrial dysfunction by regulating mitochondrial metabolism. Our results indicate that ATP5J is a key factor in regulating microglial functional transformation post-ICH by modulating mitochondrial dysfunction and metabolism, thereby positively regulate neuroinflammation. By inhibiting ATP5J, SBI following ICH could be prevented. Therefore, ATP5J could be a candidate for molecular and therapeutic target exploration to alleviate neuroinflammation post-ICH.

Project description:The neuroinflammatory response after intracerebral hemorrhage (ICH) causes a large amount of neuronal loss, and inhibiting the inflammatory response can improve the prognosis. In previous laboratory studies and clinical trials, ursolic acid (UA) inhibited the inflammatory response, but whether it can be administered to inhibit the neuroinflammatory response after cerebral hemorrhage is unknown. The aim of this study was to investigate the effects of ursolic acid after cerebral hemorrhage. Online databases were used to obtain potential therapeutic targets of ursolic acid for the treatment of cerebral hemorrhage, and possible mechanisms were analyzed by KEGG, GO, and molecular docking. A rat model of cerebral hemorrhage was established using collagenase, and an in vitro cerebral hemorrhage model was constructed by adding hemin to BV2 cell culture medium. Enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), immunofluorescence, TUNEL staining, and calcein/PI staining were used to investigate the degree of microglial M1 polarization, changes in the levels of inflammatory factors, activation of the NF-κB pathway, and changes in the indicators of cellular death after ursolic acid treatment. In addition, phorbol 12-myristate 13-acetate (PMA) was used to activate the NF-κB pathway to verify that ursolic acid exerts its anti-neuroinflammatory effects by regulating the NF-κB/NLRP3/GSDMD pathway. Network pharmacology and bioinformatics analyses revealed that ursolic acid may exert its therapeutic effects on cerebral hemorrhage through multiple pathways. Together, in vivo and in vitro experiments showed that ursolic acid inhibited microglial M1 polarization and significantly reduced the levels of p-NF-κB, GSDMD-N, cleaved caspase-1, TNF-α, IL-6, and IL-1β, which were significantly inhibited by the use of PMA. Ursolic acid inhibits microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway to alleviate neuroinflammatory responses after cerebral hemorrhage.

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Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage.

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Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage.

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