Regulatory T Cell-Microglia Crosstalk Promotes White Matter Repair after Ischemic Stroke through Osteopontin [Treg]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE171097 | GEO | 2021/05/19
REPOSITORIES: GEO
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Project description:The repair of white matter damage is of paramount importance for functional recovery after brain injuries.We report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 days after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific PPARγ knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the CNS, which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.
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Project description:Stroke involves in the interaction between central and peripheral immune systems. Skull bone marrows serve as reservoirs for immune cells in brain borders, and can rapidly respond to perturbations in the brain environment. Hence, targeting the skull bone marrow to modulate neuroimmune communications along the calvaria-meninges-brain axis would potentially improve stroke prognosis. Here, we successfully achieved cranial immunomodulation via ultraviolet (UV) irradiation of the interparietal region, which was characterized by rich marrow cavities and channels connecting the skull and meninges. Utilizing the recently-developed long-term clearing cranial window that ensured the integrity of skull, we discovered that the cranial photo-immunologic regulation (CPR) could promote cerebrovascular regeneration and aid in neurovascular repair post ischemic stroke. Single-cell transcriptome analysis revealed that meninge could be a crucial neuroimmune interface for ischemic stroke-induced immune responses. And, CPR could restore the stroke-induced alterations in cellular gene expression, especially meningeal B cells. Further we demonstrated that CPR could effectively alleviate the excessive suppression of meningeal B cell activation caused by ischemic stroke. This work opens avenues for immunoregulation through the skull-meninges-brain axis and provides valuable insights for immunomodulatory therapies in brain diseases.
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Project description:Blood monocytes/macrophages infiltrate the brain after ischemic stroke and critically influence brain injury and regeneration. We investigated stroke-induced transcriptomic changes of monocytes/macrophages by RNA sequencing profiling, using a mouse model of permanent focal cerebral ischemia. Compared to non-ischemic conditions, brain ischemia induced only moderate genomic changes in blood monocytes, but triggered robust genomic reprogramming in monocytes/macrophages invading the brain. Surprisingly, functional enrichment analysis of the transcriptome of brain macrophages revealed significant overrepresentation of biological processes linked to neurovascular remodeling, such as angiogenesis and axonal regeneration, as early as 5 days after stroke, suggesting a previously underappreciated role for macrophages in initiating post-stroke brain repair. Upstream Regulator analysis predicted peroxisome proliferator-activated receptor gamma (PPARγ) as a master regulator driving the transcriptional reprogramming in post-stroke brain macrophages. Importantly, myeloid cell-specific PPARγ knockout (mKO) mice demonstrated lower post-stroke angiogenesis and neurogenesis than wild-type mice, which correlated significantly with the exacerbation of post-stroke neurological deficits in mKO mice. Collectively, our findings reveal a novel repair-enhancing transcriptome in brain macrophages during post-stroke neurovascular remodeling. As a master switch controlling genomic reprogramming, PPARγ is a rational therapeutic target for promoting and maintaining beneficial macrophage functions, facilitating neurorestoration, and improving long-term functional recovery after ischemic stroke.
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