RhoA balances microglial reactivity and survival during neuroinflammation

Abstract

Microglia are the largest myeloid cell population in the brain. During injury, disease, or inflammation, microglia adopt different functional states primarily involved in restoring brain homeostasis. However, sustained or exacerbated microglia inflammatory reactivity can lead to brain damage. Dynamic cytoskeleton reorganization correlates with alterations of microglial reactivity driven by external cues, and proteins controlling cytoskeletal reorganization, such as the Rho GTPase RhoA, are well positioned to refine or adjust the functional state of the microglia during injury, disease, or inflammation. Here, we use multi-biosensor-based live-cell imaging approaches and tissue-specific conditional gene ablation in mice to understand the role of RhoA in microglial response to inflammation. We found that a decrease in RhoA activity is an absolute requirement for microglial metabolic reprogramming and reactivity to inflammation. However, without RhoA, inflammation disrupts Ca²⁺ and pH homeostasis, dampening mitochondrial function, worsening microglial necrosis, and triggering microglial apoptosis. Our results suggest that a minimum level of RhoA activity is obligatory to concatenate microglia inflammatory reactivity and survival during neuroinflammation.