"Momentum" Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary.
János Szentágothai Doctoral School of Neurosciences, Schools of PhD Studies, Semmelweis University, Budapest, Hungary.
J Exp Med. 2022 Mar 7;219(3). doi: 10.1084/jem.20211071. Epub 2022 Feb 24.
Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive. Here, we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. Microglia establish direct, dynamic purinergic contacts with cells in the neurovascular unit that shape CBF in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in mice, which is reiterated by chemogenetically induced microglial dysfunction associated with impaired ATP sensitivity. Hypercapnia induces rapid microglial calcium changes, P2Y12R-mediated formation of perivascular phylopodia, and microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Microglial actions modulate vascular cyclic GMP levels but are partially independent of nitric oxide. Finally, microglial dysfunction markedly impairs P2Y12R-mediated cerebrovascular adaptation to common carotid artery occlusion resulting in hypoperfusion. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation, with broad implications for common neurological diseases.
小胶质细胞是大脑中主要的免疫活性细胞，调节神经元功能，但它们在脑血流（CBF）调节中的作用仍不清楚。在这里，我们发现小胶质细胞是在生理条件下和低灌注期间调节 CBF 的重要调节剂。小胶质细胞与神经血管单元中的细胞建立直接的、动态的嘌呤能接触，在小鼠和人类中调节 CBF。令人惊讶的是，小胶质细胞缺失或小胶质细胞 P2Y12 受体（P2Y12R）阻断会显著损害小鼠的神经血管偶联，这与与 ATP 敏感性受损相关的化学遗传诱导的小胶质细胞功能障碍相重复。高碳酸血症诱导小胶质细胞钙变化、P2Y12R 介导的血管周足形成和小胶质细胞腺苷产生，而小胶质细胞耗竭会降低脑 pH 值并损害高碳酸血症诱导的血管扩张。小胶质细胞的作用调节血管环鸟苷酸水平，但部分独立于一氧化氮。最后，小胶质细胞功能障碍显著损害 P2Y12R 介导的常见颈动脉闭塞后脑血管适应，导致低灌注。因此，我们的数据揭示了小胶质细胞在 CBF 调节中的一个以前未被认识的作用，这对常见的神经疾病具有广泛的意义。
