Unveiling the Functional Role of KIF21B in Microglia Inflammatory Response

Microglia are brain immune cells that maintain homeostasis and respond to injury, changing cell morphology to drive inflammation, migration, and phagocytosis. This study examined the role of the kinesin KIF21B in microglial activation, demonstrating for the first time its expression in microglial cells in two in vivo neuroinflammatory models: TBI (focal inflammation) and LPS administration (diffuse inflammation). While TBI provoked a significant increase in KIF21B/Iba1 colocalization in the tissue around the lesion exclusively in females, LPS administration did not alter KIF21B expression in either sex. Given the importance of cytoskeleton remodeling for microglial migration and phagocytosis, this work investigates whether KIF21B contributes to these actions. Downregulating KIF21B in primary cultured mouse microglia had sex-specific effects. In females, KIF21B silencing reduced both migratory capacity and phagocytosis of E. coli-coated spheres and neuronal debris. In males, it exacerbated migration and selectively increased neuronal debris phagocytosis, while E. coli-coated sphere uptake remained unaffected. These functional differences were accompanied by sex-dependent morphological alterations, quantified through area, circularity, Feret's diameter, and perimeter: KIF21B silencing blocked the transition to amoeboid morphology in females while inducing hyperpolarized elongation in males. Finally, LPS treatment increased KIF21B colocalization with microtubules and reduced its colocalization with F-actin in females, while neither interaction was significantly altered in males. Overall, the findings suggest that KIF21B regulates microglial function in a sex-dependent manner through its effects on cytoskeletal organization.