Bruton's tyrosine kinase (BTK) plays a key role in the inflammatory response in many diseases. However, its specific function and underlying mechanisms in intracerebral hemorrhage (ICH) remain unclear. Here, we used a mouse ICH model and transcriptomic datasets to investigate the role and mechanism of BTK in neuroinflammation after ICH. Inhibiting BTK with ibrutinib alleviated ICH-induced neurological deficits and reduced the expression of inflammatory markers in mice. Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis of RNA-sequencing data from ICH and control mice identified Btk as a hub gene in the green module (ranked 10th by kWithin). Also, 12 hub genes that strongly interacted with BTK were identified within the key gene module; all of them are critically involved in inflammatory processes. Single cell RNA-sequencing analysis revealed that microglia were the predominant BTK-expressing immune cells in the mouse brain, expressing 76. 4% of total BTK in sham mice and 83. 7% in ICH mice. Microglia from ICH mice were further stratified into BTKₕigh and BTKₗow subpopulations. Enrichment analysis of differentially expressed genes (DEGs) between these groups showed that a substantial proportion of the top 30 enriched pathways (12 for GO and 20 for KEGG) were immune-related. Gene set enrichment analysis (GSEA) demonstrated that four anti-inflammatory and phagocytosis-related pathways were significantly downregulated in BTKₕigh microglia compared with BTKₗow microglia (all P < 0. 001). Gene set variation analysis (GSVA) further found differential activation of multiple immune pathways between the two subpopulations. In addition, six microglia polarization scores revealed that BTKₕigh microglia preferentially polarized toward M1 and M2b phenotypes, whereas BTKₗow microglia favored M2 (M2a, M2c) states (all P < 0. 0001). Finally, intercellular communication analysis indicated that BTK promoted signaling between microglia and other immune cells, both globally and within specific inflammatory pathways. In conclusion, our findings show that BTK is a critical driver of post-ICH neuroinflammation. This effect is mediated, at least in part, through Btk-associated hub genes and through modulation of microglial immune pathway activation, polarization state, and intercellular communication.
Xia et al. (Mon,) studied this question.
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