Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal.
Cell Death Dis. 2023 Oct 20;14(10):690. doi: 10.1038/s41419-023-06217-w.
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 Ca 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.
小胶质细胞是大脑中最大的髓系细胞群体。在损伤、疾病或炎症期间，小胶质细胞采用不同的功能状态，主要涉及恢复大脑内稳态。然而，持续或加剧的小胶质细胞炎症反应可导致脑损伤。动态细胞骨架重组与小胶质细胞反应性的改变相关，这些改变由外部线索驱动，并且控制细胞骨架重组的蛋白质，如 Rho GTPase RhoA，在损伤、疾病或炎症期间精细调整或调节小胶质细胞的功能状态方面具有重要作用。在这里，我们使用基于多生物传感器的活细胞成像方法和小鼠组织特异性条件性基因敲除，来了解 RhoA 在小胶质细胞对炎症反应中的作用。我们发现，RhoA 活性的降低是小胶质细胞代谢重编程和对炎症反应性的绝对要求。然而，没有 RhoA，炎症会破坏 Ca 和 pH 平衡，抑制线粒体功能，使小胶质细胞坏死恶化，并引发小胶质细胞凋亡。我们的结果表明，在神经炎症期间，RhoA 活性的最低水平对于串联小胶质细胞炎症反应性和存活是必需的。
