Spi1 regulates the microglial/macrophage inflammatory response via the PI3K/AKT/mTOR signaling pathway after intracerebral hemorrhage

Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.

A novel phenotype of B cells associated with enhanced phagocytic capability and chemotactic function after ischemic stroke

Accumulating evidence has demonstrated the involvement of B cells in neuroinflammation and neuroregeneration.However,the role of B cells in ischemic stroke remains unclear.In this study,we identified a novel phenotype of macrophage-like B cells in brain-infiltrating immune cells expressing a high level of CD45.Macrophage-like B cells chara cterized by co-expression of B-cell and macrophage markers,showed stronger phagocytic and chemotactic functions compared with other B cells and showed upregulated expression of phagocytosis-related genes.Gene Ontology analysis found that the expression of genes associated with phagocytosis,including phagosome-and lysosome-related genes,was upregulated in macrophage-like B cells.The phagocytic activity of macrophage-like B cells was ve rified by immunostaining and three-dimensional reconstruction,in which TREM2-labeled macrophage-like B cells enwrapped and internalized myelin debris after cerebral ischemia.Cell-cell interaction analysis revealed that macrophage-like B cells released multiple chemokines to recruit peripheral immune cells mainly via CCL pathways.Single-cell RNA sequencing showed that the transdiffe rentiation to macrophage-like B cells may be induced by specific upregulation of the transcription factor CEBP fa mily to the myeloid lineage and/or by downregulation of the transcription factor Pax5 to the lymphoid lineage.Furthermore,this distinct B cell phenotype was detected in brain tissues from mice or patients with traumatic brain injury,Alzheimer’s disease,and glioblastoma.Overall,these results provide a new perspective on the phagocytic capability and chemotactic function of B cells in the ischemic brain.These cells may serve as an immunotherapeutic target for regulating the immune response of ischemic stroke.

Age-Related Alterations in Peripheral Immune Landscape with Magnified Impact on Post-Stroke Brain

Immunosenescence refers to the multifaceted and profound alterations in the immune system brought about by aging,exerting complex influences on the pathophysiological processes of diseases that manifest upon it.Using a combination of single-cell RNA sequencing,cytometry by time of flight,and various immunological assays,we investigated the characteristics of immunosenescence in the peripheral blood of aged mice and its impact on the cerebral immune environment after ischemic stroke.Our results revealed some features of immunosenescence.We observed an increase in neutrophil counts,concurrent with accelerated neutrophil aging,characterized by altered expression of aging-associated markers like CD62L and consequential changes in neutrophil-mediated immune functions.Monocytes/macrophages in aged mice exhibited enhanced antigen-presentation capabilities.T cell profiles shifted from naive to effector or memory states,with a specific rise in T helper 1 cells and T helper 17 cells subpopulations and increased regulatory T cell activation in CD4 T cells.Furthermore,regulatory CD8 T cells marked by Klra decreased with aging,while a subpopulation of exhausted-like CD8 T cells expanded,retaining potent immunostimulatory and proinflammatory functions.Critically,these inherent disparities not only persisted but were further amplified within the ischemic hemispheres following stroke.In summary,our comprehensive insights into the key attributes of peripheral immunosenescence provide a vital theoretical foundation for understanding not only ischemic strokes but also other age-associated diseases.