Suppression of microglial activation and monocyte infiltration ameliorates cerebellar hemorrhage induced-brain injury and ataxia

Xie, Shutao; Chen, Ao-Xue; Song, Bo; Fan, Jia; Li, Wei; Xing, Zhen; Peng, Shi-Yu; Zhang, Qipeng; Dong, Lei; Yan, Chao; Zhang, Xiaoyang; Wang, Jianjun; Zhu, Jing-Ning

doi:10.1016/j.bbi.2020.07.027

Cited by 20 publications

(7 citation statements)

References 67 publications

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“…In primary microglia (in vitro) and neuropathic pain rat models (in vivo), minocycline suppressed the upregulation of CCL2 and CCR2 [24]. In a mouse model of cerebellar hemorrhage, infiltration of monocytes and macrophages into the cerebellum was decreased by minocycline treatment [25]. In the current study, significant inhibition of the number of CCR2-RFP positive cells in both the retina and RPE was observed in flat-mounts.…”

Section: Plos Onesupporting

confidence: 56%

Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa

et al. 2021

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Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)−/−Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.

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Section: Plos Onesupporting

confidence: 56%

Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa

et al. 2021

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“…To test the effects of CCL2 upon HIV brain disease by an alternate approach, we employed bindarit that inhibits transcription of CCL2 through interference with NFkB activation at the CCL2 promoter 46 . In mice, bindarit blocks expression of CCL2 RNA and protein and prevents in ammatory monocyte entry into the brain 47 as well as preventing pathological microglia activation during impaired neonatal brain development 48 . C57BL/6 mice were pretreated with bindarit one day before EcoHIV infection by IP injection and then daily through RAWM testing at Day 25 until euthanasia (Fig.…”

Section: Block Of Ccl2 Synthesis Prevents Development Of Hiv-ncimentioning

confidence: 99%

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Kim

Hadas

Kelschenbach

et al. 2023

Preprint

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HIV enters the brain within days of infection causing neurocognitive impairment (NCI) in up to half of infected people despite suppressive antiretroviral therapy. The virus is believed to enter the brain in infected monocytes through chemotaxis to the major monocyte chemokine, CCL2, but direct demonstration of the role of CCL2 in NCI pathogenesis in vivo is lacking. We addressed this question during infection of conventional or CCL2 knockout mice with EcoHIV in which NCI can be verified in behavioral tests. NCI develops gradually during EcoHIV infection of mice, with chronic cognitive disease starting 25 days after infection. CCL2 knockout mice infected by intraperitoneal injection of virus failed to develop brain infection and NCI. However, when EcoHIV was directly injected into the brain, CCL2 knockout mice developed NCI. Knockout of CCL2 or its principal receptor, CCR2, slightly reduced macrophage infection in culture. Treatment of mice prior to and during EcoHIV infection with the CCL2 transcriptional inhibitor, bindarit, prevented brain infection and NCI, and reduced macrophage infection. In contrast, bindarit treatment of mice four weeks after infection affected neither brain virus burden nor NCI, suggesting that once established, brain disease was independent of CCL2. Our results indicate that HIV enters the brain mainly through infected monocytes but that resident brain cells are sufficient to maintain NCI. A conclusion from these findings is that NCI therapy must act within the brain. .

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“…As resident immune cells in the central nervous system, microglia are one of the first responders in CNS injuries ( Greenhalgh et al, 2020 ; Xie et al, 2020 ). Currently, numerous studies have suggested that activated microglia with distinct phenotypes are double-edged swords in ischemic stroke ( Liu ZJ.…”

Section: Introductionmentioning

confidence: 99%

MLIF Modulates Microglia Polarization in Ischemic Stroke by Targeting eEF1A1

et al. 2021

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Monocyte locomotion inhibitory factor (MLIF) is a heat-stable pentapeptide from Entamoeba histolytica. Our previous study found that MLIF protects against ischemic stroke in rats and mice and exerts a neuroprotection effect in human neuroblastoma SH-SY5Y cells. Microglia/macrophage polarization has been proven to be vital in the pathology of ischemic stroke. Nevertheless, whether MLIF is able to modulate microglia/macrophage polarization remains unclear. We performed middle cerebral artery occlusion (MCAO) on C57BL/6J male mice and induced cultured BV2 microglia by oxygen-glucose deprivation (OGD), respectively. Immunfluorescence was utilized to detect the M1/2 markers, such as CD206 and CD16/32. qPCR and ELISA were used to detect the signature gene change of M1/2. The MAPK and NF-κB pathway associated proteins were measured by Western blot. To identify the protein target of MLIF, a pull-down assay was performed. We found that MLIF promoted microglia transferring from a “sick” M1 phenotype to a “healthy” M2 phenotype in vivo or in vitro. Furthermore, we proved that eukaryotic elongation factor 1A1 (eEF1A1) was involved in the modulation of microglia/macrophage polarization. Knocking down eEF1A1 by siRNA exhibited the M1 promotion effect and M2 inhibition effect. Taken together, our results demonstrated MLIF modulated microglia/macrophage polarization by targeting eEF1A1 in ischemic stroke.

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Suppression of microglial activation and monocyte infiltration ameliorates cerebellar hemorrhage induced-brain injury and ataxia

Cited by 20 publications

References 67 publications

Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa

Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

MLIF Modulates Microglia Polarization in Ischemic Stroke by Targeting eEF1A1

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