RGD Reference Report - Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE. - Rat Genome Database

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

Authors: Hu, Xiao  Li, Shirong  Doycheva, Desislava Met  Huang, Lei  Lenahan, Cameron  Liu, Rui  Huang, Juan  Xie, Shucai  Tang, Jiping  Zuo, Gang  Zhang, John H 
Citation: Hu X, etal., J Neuroinflammation. 2020 Jun 10;17(1):182. doi: 10.1186/s12974-020-01862-w.
RGD ID: 151665765
Pubmed: PMID:32522286   (View Abstract at PubMed)
PMCID: PMC7285566   (View Article at PubMed Central)
DOI: DOI:10.1186/s12974-020-01862-w   (Journal Full-text)


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 (PKCε), 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-PKCε, and p-CREB, but inhibited the activation of neutrophil infiltration, and downregulated the expressions of IL-1β and TNF-α. 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/PKCε/CREB signaling pathway after HI. These results suggest that rh-CSF1 may serve as a potential therapeutic approach to ameliorate injury in HIE patients.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Brain Hypoxia-Ischemia exacerbatesISOCsf1r (Rattus norvegicus)151665765; 151665765 RGD 
Brain Hypoxia-Ischemia exacerbatesIMP 151665765 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to hypoxia  IEP 151665765 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Csf1r  (colony stimulating factor 1 receptor)

Genes (Mus musculus)
Csf1r  (colony stimulating factor 1 receptor)

Genes (Homo sapiens)
CSF1R  (colony stimulating factor 1 receptor)


Additional Information