Dataset Information

Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKC? pathway in a rat model of neonatal HIE.

ABSTRACT:

Background

Hypoxic-ischemic encephalopathy (HIE) is a life-threatening cerebrovascular disease. Neuroinflammation plays an important role in the pathogenesis of HIE, in which microglia are key cellular mediators in the regulation of neuroinflammatory processes. Colony-stimulating factor 1 (CSF1), a specific endogenous ligand of CSF1 receptor (CSF1R), is crucial in microglial growth, differentiation, and proliferation. Recent studies showed that the activation of CSF1R with CSF1 exerted anti-inflammatory effects in a variety of nervous system diseases. This study aimed to investigate the anti-inflammatory effects of recombinant human CSF1 (rh-CSF1) and the underlying mechanisms in a rat model of HIE.

Methods

A total of 202 10-day old Sprague Dawley rat pups were used. HI was induced by the right common carotid artery ligation with subsequent exposure of 2.5-h hypoxia. At 1?h and 24?h after HI induction, exogenous rh-CSF1 was administered intranasally. To explore the underlying mechanism, CSF1R inhibitor, BLZ945, and phospholipase C-gamma 2 (PLCG2) inhibitor, U73122, were injected intraperitoneally at 1?h before HI induction, respectively. Brain infarct area, brain water content, neurobehavioral tests, western blot, and immunofluorescence staining were performed.

Results

The expressions of endogenous CSF1, CSF1R, PLCG2, protein kinase C epsilon type (PKC?), and cAMP response element-binding protein (CREB) were gradually increased after HIE. Rh-CSF1 significantly improved the neurological deficits at 48?h and 4?weeks after HI, which was accompanied by a reduction in the brain infarct area, brain edema, brain atrophy, and neuroinflammation. Moreover, activation of CSF1R by rh-CSF1 significantly increased the expressions of p-PLCG2, p-PKC?, and p-CREB, but inhibited the activation of neutrophil infiltration, and downregulated the expressions of IL-1? and TNF-?. Inhibition of CSF1R and PLCG2 abolished these neuroprotective effects of rh-CSF1 after HI.

Conclusions

Our findings demonstrated that the activation of CSF1R by rh-CSF1 attenuated neuroinflammation and improved neurological deficits after HI. The anti-inflammatory effects of rh-CSF1 partially acted through activating the CSF1R/PLCG2/PKC?/CREB signaling pathway after HI. These results suggest that rh-CSF1 may serve as a potential therapeutic approach to ameliorate injury in HIE patients.

SUBMITTER: Hu X

PROVIDER: S-EPMC7285566 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE.

Hu Xiao X Li Shirong S Doycheva Desislava Met DM Huang Lei L Lenahan Cameron C Liu Rui R Huang Juan J Xie Shucai S Tang Jiping J Zuo Gang G Zhang John H JH

Journal of neuroinflammation 20200610 1

<h4>Background</h4>Hypoxic-ischemic encephalopathy (HIE) is a life-threatening cerebrovascular disease. Neuroinflammation plays an important role in the pathogenesis of HIE, in which microglia are key cellular mediators in the regulation of neuroinflammatory processes. Colony-stimulating factor 1 (CSF1), a specific endogenous ligand of CSF1 receptor (CSF1R), is crucial in microglial growth, differentiation, and proliferation. Recent studies showed that the activation of CSF1R with CSF1 exerted a ...[more]

PMID: 32522286

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