Abstract
In traumatic brain injury (TBI), mechanical injury results in instantaneous tissue damages accompanied by subsequent pro-inflammatory cascades composed of microgliosis and astrogliosis. However, the interactive roles between microglia and astrocytes during the pathogenesis of TBI remain unclear and sometimes debatable. In this study, we used a forebrain stab injury mouse model to investigate the pathological role of reactive astrocytes in cellular and molecular changes of inflammatory response following TBI. In the ipsilateral hemisphere of stab-injured brain, monocyte infiltration and neuronal loss, as well as increased elevated astrogliosis, microglia activation and inflammatory cytokines were observed. To verify the role of reactive astrocytes in TBI, local and partial ablation of astrocytes was achieved by stereotactic injection of diphtheria toxin in the forebrain of Aldh1l1-CreERT2::Ai9::iDTR transgenic mice which expressed diphtheria toxin receptor (DTR) in astrocytes after tamoxifen induction. This strategy achieved about 20% of astrocytes reduction at the stab site as validated by immunofluorescence co-staining of GFAP with tdTomato-positive astrocytes. Interestingly, reduction of astrocytes showed increased microglia activation and monocyte infiltration, accompanied with increased severity in stab injury-induced neuronal loss when compared with DTR−/− mice, together with elevation of inflammatory chemokines such as CCL2, CCL5 and CXCL10 in astrogliosis-reduced mice. Collectively, our data verified the interactive role of astrocytes as an immune modulator in suppressing inflammatory responses in the injured brain.
Graphical Abstract
Schematic diagram shows monocyte infiltration and neuronal loss, as well as increased elevated astrogliosis, microglia activation and chemokines were observed in the injured site after stab injury. Local and partial ablation of astrocytes led to increased microglia activation and monocyte infiltration, accompanied with increased severity in neuronal loss together with elevation of inflammatory chemokines as compared with control mice subjected stab injury.
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Data Availability
The datasets used and analyzed during the course of this study are available from the corresponding author upon reasonable request.
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Funding
This study was funded by the National Natural Science Foundation of China (No. 81925031, 81820108026), Guangzhou Science and Technology Program key projects (202007030001) to Yamei Tang; National Natural Science Foundation of China (No. 82103775) to Zhongshan Shi; National Natural Science Foundation of China (No. 81972967), Guangdong Science and Technology Department (2020B1212060018), Natural Science Foundation of Guangdong Province (2019A1515011754) to Wei-Jye Lin; National Natural Science Foundation of China (81872549), and Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence Fund (2019012) to Yi Li; National Natural Science Foundation of China (No. 82003389) to Honghong Li; Youth Program of National Natural Science Foundation of China (No. 81801229) to Yongteng Xu.
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YT and MZ conceptualized and designed the study, and revised the manuscript. XH, SL and ZS bred the transgenic mice, performed the stab model, immunofluorescence and qPCR experiments, and wrote the first draft of manuscript. WL, YY, YL, HL and YX collected and analyzed the data and revised the manuscript. All authors read and approved the final manuscript.
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Hu, X., Li, S., Shi, Z. et al. Partial Ablation of Astrocytes Exacerbates Cerebral Infiltration of Monocytes and Neuronal Loss After Brain Stab Injury in Mice. Cell Mol Neurobiol 43, 893–905 (2023). https://doi.org/10.1007/s10571-022-01224-5
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DOI: https://doi.org/10.1007/s10571-022-01224-5