Reproducible Interferon-Centered Microglial Response at 7 Days After Traumatic Brain Injury: A Transcriptomic Meta-Analysis with Focus on the BTK/NOX2 Panel

Traumatic brain injury (TBI) drives sustained microglial activation and secondary neurodegeneration. The Bruton’s tyrosine kinase (BTK)–NADPH oxidase 2 (NOX2) axis has been proposed as a convergent node, but transcriptional evidence has largely been derived from individual studies. Our primary aim was to characterize the microglial response at 7 days post-injury, and our secondary aim was to evaluate BTK/NOX2-associated genes within this response. We performed a random-effects meta-analysis (metafor, REML) of four independent mouse microglial RNA-seq datasets (16,636 genes). Differential expression estimates were pooled across datasets and characterized by protein–protein interaction network analysis, functional enrichment (GO, Reactome, KEGG), weighted gene co-expression analysis, and gene set enrichment analysis. A curated 14-gene BTK/NOX2 panel was tested at the individual-gene and aggregate levels. The meta-analysis identified 160 significant genes at 7 days (117 upregulated, 43 downregulated). Interferon signaling was the most consistent program, supported by gene set enrichment, over-representation analysis, and the largest network cluster. It comprised antigen presentation, a lipid-handling signature resembling disease-associated microglia (Lpl, log2FC = 3.86), and partially reduced homeostatic genes. Within the panel, Cybb was the only significant gene (log2FC = 1.66, adjusted p = 0.019) that increased in the same direction in all four datasets, whereas no significant change was detected at the panel level, although statistical power was limited by the small number of genes (n = 14). The 7-day microglial response is interferon-centered and reproducible, and the BTK/NOX2 signal is limited to a transcript-level increase in Cybb.