Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia

Cao, Qian; Chen, Jian; Zhang, Zhi; Shu, Shu; Qian, Yi; Yang, Lixuan; Xu, Lushan; Zhang, Yuxin; Bao, Xinyu; Xia, Shengnan; Yang, Haiyan; Xu, Yun; Qiu, Siqi

doi:10.1186/s12974-023-02780-3

Cited by 20 publications

(5 citation statements)

References 41 publications

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“…1 ). These results are consistent with previous research [ 33 , 34 ]. Our data could not exclude the possibility that CXCR2 was also expressed in neurons following TBI.…”

Section: Resultssupporting

confidence: 94%

“…Under normal conditions, CXCR2 is mainly expressed in neurons [ 33 ]. Also, immunofluorescence staining demonstrated that CXCR2 was highly expressed in activated microglia of chronic ischemia-induced white matter injury [ 34 ]. Of particular noteworthy, we discovered that administration of competitive CXCR2 antagonist SB332235 resulted in the substantial decrease in CXCL1 and CXCR2 levels at 3 days post TBI.…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotective Effects of CXCR2 Antagonist SB332235 on Traumatic Brain Injury Through Suppressing NLRP3 Inflammasome

Zhao,

Zhou,

Chen

et al. 2023

Neurochem Res

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The inflammatory process mediated by nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain comprising 3 (NLRP3) inflammasome plays a predominant role in the neurological dysfunction following traumatic brain injury (TBI). SB332235, a highly selective antagonist of chemokine receptor 2 (CXCR2), has been demonstrated to exhibit anti-inflammatory properties and improve neurological outcomes in the central nervous system. We aimed to determine the neuroprotective effects of SB332235 in the acute phase after TBI in mice and to elucidate its underlying mechanisms. Male C57BL/6J animals were exposed to a controlled cortical impact, then received 4 doses of SB332235, with the first dose administered at 30 min after TBI, followed by additional doses at 6, 24, and 30 h. Neurological defects were assessed by the modified neurological severity score, while the motor function was evaluated using the beam balance and open field tests. Cognitive performance was evaluated using the novel object recognition test. Brain tissues were collected for pathological, Western blot, and immunohistochemical analyses. The results showed that SB332235 significantly ameliorated TBI-induced deficits, including motor and cognitive impairments. SB332235 administration suppressed expression of both CXCL1 and CXCR2 in TBI. Moreover, SB332235 substantially mitigated the augmented expression levels and activation of the NLRP3 inflammasome within the peri-contusional cortex induced by TBI. This was accompanied by the blocking of subsequent production of pro-inflammatory cytokines. Additionally, SB332235 hindered microglial activity induced by TBI. These findings confirmed the neuroprotective effects of SB332235 against TBI, and the involved mechanisms were in part due to the suppression of NLRP3 inflammasome activity. This study suggests that SB332235 may act as an anti-inflammatory agent to improve functional outcomes in brain injury when applied clinically.

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“…1 ). These results are consistent with previous research [ 33 , 34 ]. Our data could not exclude the possibility that CXCR2 was also expressed in neurons following TBI.…”

Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of CXCR2 Antagonist SB332235 on Traumatic Brain Injury Through Suppressing NLRP3 Inflammasome

Zhao,

Zhou,

Chen

et al. 2023

Neurochem Res

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“…Myelin debris preparation followed established protocols. 30 , 31 In summary, mice were humanely euthanized, and brain samples were isolated and cut into approximately 5 × 5 × 5 mm 3 sections. The solution was transferred to a 0.83 M sucrose solution.…”

Section: Methodsmentioning

confidence: 99%

“…Primary oligodendrocytes originate from the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) based on previous experiments. 31 , 32 OPCs were obtained from newborn C57BL/6 pups (postnatal 0–2; P0–2). Following the removal of the meninges, cortical tissues were mechanically minced and dissociated.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of ADORA3 promotes microglial phagocytosis and alleviates chronic ischemic white matter injury

Xu,

Tang,

Zhou

et al. 2024

CNS Neurosci Ther

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BackgroundAdenosine A3 receptor (ADORA3) belongs to the adenosine receptor families and the role of ADORA3 in vascular dementia (VaD) is largely unexplored. The present study sought to determine the therapeutic role of ADORA3 antagonist in a mouse model of VaD.MethodsThe GSE122063 dataset was selected to screen the differential expression genes and pathways between VaD patients and controls. A mouse model of bilateral carotid artery stenosis (BCAS) was established. The cognitive functions were examined by the novel object recognition test, Y maze test, and fear of conditioning test. The white matter injury (WMI) was examined by 9.4 T MRI, western blot, and immunofluorescence staining. The mechanisms of ADORA3‐regulated phagocytosis by microglia were examined using qPCR, western blot, dual immunofluorescence staining, and flow cytometry.ResultsThe expression of ADORA3 was elevated in brain tissues of VaD patients and ADORA3 was indicated as a key gene for VaD in the GSE122063. In BCAS mice, the expression of ADORA3 was predominantly elevated in microglia in the corpus callosum. ADORA3 antagonist promotes microglial phagocytosis to myelin debris by facilitating cAMP/PKA/p‐CREB pathway and thereby ameliorates WMI and cognitive impairment in BCAS mice. The therapeutic effect of ADORA3 antagonist was partially reversed by the inhibition of the cAMP/PKA pathway.ConclusionsADORA3 antagonist alleviates chronic ischemic WMI by modulating myelin clearance of microglia, which may be a potential therapeutic target for the treatment of VaD.

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“…A stereotaxic intracranial injection was performed following established protocols [ 19 ]. The injection site for the corpus callosum (CC) was determined based on the brain map, with coordinates of 1 mm lateral from the midline, 0.8 mm anterior from the bregma, and 2.2 mm deep from the bregma.…”

Section: Methodsmentioning

confidence: 99%

MFG-E8 Alleviates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Phagocytosing Myelin Debris and Promoting Remyelination

Dong,

Zhang,

Shu

et al. 2023

Neurosci. Bull.

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Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury. Microglia phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white matter. However, milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a microglial phagocytosis-related protein, has not been well studied in hypoperfusion-related cognitive dysfunction. We found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis (BCAS). MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral tests. In addition, we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron microscopy. Meanwhile, MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after BCAS. Moreover, in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via the αVβ3/αVβ5/Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes. Interestingly, we found that MFG-E8 was mainly derived from astrocytes, not microglia. Our findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.

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Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia

Cited by 20 publications

References 41 publications

Neuroprotective Effects of CXCR2 Antagonist SB332235 on Traumatic Brain Injury Through Suppressing NLRP3 Inflammasome

Neuroprotective Effects of CXCR2 Antagonist SB332235 on Traumatic Brain Injury Through Suppressing NLRP3 Inflammasome

Inhibition of ADORA3 promotes microglial phagocytosis and alleviates chronic ischemic white matter injury

MFG-E8 Alleviates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Phagocytosing Myelin Debris and Promoting Remyelination

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