Kinase signaling networks governing neuroinflammatory glial phenotypes: Current understanding and emerging targets

Glial cells, particularly microglia and astrocytes, orchestrate the neuroinflammatory response in the central nervous system (CNS) through sequential phenotypic changes encompassing inflammatory activation, migration, phagocytosis, and tissue remodeling. Kinases serve as central regulators of these processes, yet systematic investigations of kinase signaling networks in brain glia have been remarkably limited compared to oncology or peripheral immunology. To address this gap, we developed a multiplexed kinome-wide small interfering RNA screening platform that simultaneously interrogates 623 kinases across four distinct neuroinflammatory glial phenotypes. This approach identified distinct kinase signaling networks governing glial activation, migration, phagocytosis, and cell survival, and revealed that the same signaling pathway can exert opposing effects depending on the phenotype examined. Most unexpectedly, T-cell receptor signaling components were enriched among kinases promoting glial activation, leading to the identification of interleukin-2-inducible T-cell kinase (ITK)-a canonical adaptive immune kinase-as a potent regulator of microglial inflammatory activation. Subsequent validation demonstrated that microglial ITK drives neuroinflammation and behavioral deficits in a traumatic brain injury model through the Vav1-PLC-γ-NF-κB axis, with confirmatory evidence from brain tissues of patients with chronic traumatic encephalopathy and human microglial cells. Multiple intracellular kinase cascades-including the TLR-TAK1-IKK, MAPK, PI3K-Akt-mTOR, JAK-STAT, and SYK-BTK pathways-converge on key transcription factors such as NF-κB, AP-1, STAT1/3, and NFAT to shape glial inflammatory gene expression, and extensive cross-talk between these cascades adds further complexity to the neuroinflammatory response. Viewed alongside the emergence of Bruton's tyrosine kinase as a therapeutic target in microglia-driven multiple sclerosis, these findings suggest that the Tec kinase family constitutes a previously unrecognized signaling hub in brain innate immunity. This review discusses how systematic kinome screening reshapes our understanding of glial biology and highlights the translational potential of microglial ITK as a disease-relevant therapeutic target.