Abstract
Neurons have inherent competence to regrow following injury, although not spontaneously. Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by resident microglia and infiltrating peripheral macrophages. Microglia are the first reactive glial population after SCI and participate in recruitment of monocyte-derived macrophages to the lesion site. Both positive and negative influence of microglia and macrophages on axonal regeneration had been reported after SCI, raising the issue whether their response depends on time post-lesion or different lesion severity. We analyzed molecular alterations in microglia at several time-points after different SCI severities using RNA-sequencing. We demonstrate that activation of microglia is time-dependent post-injury but is independent of lesion severity. Early transcriptomic response of microglia after SCI involves proliferation and neuroprotection, which is then switched to neuroinflammation at later stages. Moreover, SCI induces an autologous microglial expression of astrocytic markers with over 6% of microglia expressing glial fibrillary acidic protein and vimentin from as early as 72 h post-lesion and up to 6 weeks after injury. We also identified the potential involvement of DNA damage and in particular tumor suppressor gene breast cancer susceptibility gene 1 (Brca1) in microglia after SCI. Finally, we established that BRCA1 protein is specifically expressed in non-human primate spinal microglia and is upregulated after SCI. Our data provide the first transcriptomic analysis of microglia at multiple stages after different SCI severities. Injury-induced microglia expression of astrocytic markers at RNA and protein levels demonstrates novel insights into microglia plasticity. Finally, increased microglia expression of BRCA1 in rodents and non-human primate model of SCI, suggests the involvement of oncogenic proteins after CNS lesion.
Highlights
Spinal cord injury (SCI) is a devastating condition with clinical symptoms that depend on both the anatomical level of the injury and the severity of the lesion
We identified the potential involvement of DNA damage pathway and BRCA1 in microglia following SCI
The breakdown of blood spinal cord barrier induced by SCI permits the infiltration of blood monocytes, activated macrophages result from a mixed population of resident microglia and infiltrating blood-derived macrophages (Popovich et al, 1996)
Summary
Spinal cord injury (SCI) is a devastating condition with clinical symptoms that depend on both the anatomical level of the injury and the severity of the lesion. Other studies have reported both positive (Shechter et al, 2009) and negative (Popovich et al, 1999) influence of infiltrating monocyte-derived macrophages on functional recovery after SCI. Together, these studies highlight positive and negative influence of CNS resident microglia and peripheral infiltrating macrophages after SCI. Whether these dual roles are due to differences in time post-injury, lesion severity or both remains unclear and the precise molecular mechanisms that control the positive and negative roles of activated microglia post-injury are poorly understood
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