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bioRxiv · 10.64898/2026.03.04.709243

BTK promotes neuroinflammation by interacting with hub genes and modulating microglia following intracerebral hemorrhage

Xia, S.·Chen, G.
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Abstract

Brutons tyrosine kinase (BTK) has been reported to be important in the inflammatory response in many diseases. However, its role and explicit mechanisms in intracerebral hemorrhage (ICH) remain unclear. Here, we used a mouse ICH model and transcriptomic datasets to explore the effect of BTK on neuroinflammation after ICH. Inhibiting BTK with ibrutinib alleviated ICH-induced neurological deficits and neuroinflammation in mice. After analyzing RNA-sequencing data of ICH and control mice by weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis, we found that Btk was a hub gene in the green dynamic module. Also, 12 hub genes that closely interacted with BTK were identified in the key gene module, all having a critical role in the inflammatory process. Then, single cell RNA-sequencing data analysis showed that microglia were the immune cells that expressed the most BTK in the mouse brain. After dividing microglia in ICH mice into BTK_high and BTK_low groups, GO/KEGG enrichment analyses of differentially expressed genes (DEGs) between these two microglia groups revealed that most of the top 30 enriched pathways were immune-related. Then, gene set enrichment analysis (GSEA) of the BTK_high and BTK_low microglia showed that the expression levels of four anti-inflammatory and phagocytosis-related pathways were significantly lower in the BTK_high microglia than in the BTK_low microglia. Furthermore, gene set variation analysis (GSVA) demonstrated that multiple immune pathways were expressed differentially between the two microglia groups. Also, six microglia polarization scores were calculated, and the results showed that the BTK_high microglia tend to polarize towards M1 and M2b states, while the BTK_high microglia towards M2 (M2a, M2c) states. Finally, intercellular communication analysis was conducted, and BTK was revealed to promote communication between microglia and other immune cells both at the general level and in specific inflammatory pathways. In conclusion, our study showed that BTK is critical in promoting post-ICH neuroinflammation, at least partly by interacting with Btk-related hub genes and modulating microglias immune pathways, polarization, and intercellular communication.

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Xia, S., Chen, G.. 2026-03-06. BTK promotes neuroinflammation by interacting with hub genes and modulating microglia following intracerebral hemorrhage. https://doi.org/10.64898/2026.03.04.709243

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