Polarized microtubule remodeling transforms the morphology of reactive microglia cells and drives cytokine release

Microglial reactivity is a pathological hallmark in many neurodegenerative diseases. During stimulation, microglia undergo complex morphological changes, including loss of their characteristic ramified morphology, which is routinely used to detect and quantify inflammation in the brain. However, the underlying molecular mechanisms and the relation between microglial morphology and their pathophysiological function are unknown. Here, proteomic profiling of lipopolysaccharide (LPS)-reactive microglia identified microtubule remodeling pathways as an early factor that drives the morphological change and subsequently controls cytokine responses. We found that LPS-reactive microglia reorganize their microtubules to form a stable and centrosomally anchored array to facilitate efficient cytokine trafficking and release. We identified cyclin-dependent kinase 1 (Cdk-1) as a critical upstream regulator of microtubule remodeling and morphological change in-vitro and in-situ. Cdk-1 inhibition also rescued tau and amyloid fibril-induced microglia changes. These results demonstrate a critical role for microtubule dynamics and reorganization in microglial reactivity and modulating cytokine-mediated inflammatory responses. Overall design: To investigate the effect of LPS on microglia, primary murine microglia were treated with LPS (5 µg/ml) or vehicle control (n = 4 per condition). 24-hours later, total RNA was isolated and subjected to RNA-sequencing.