Diverse Inflammatory Response After Cerebral Microbleeds Includes Coordinated Microglial Migration and Proliferation.
Diverse Inflammatory Response After Cerebral Microbleeds Includes Coordinated Microglial Migration and Proliferation.
复制标题
DOI：
10.1161/strokeaha.117.020461
复制
发表时间：
2018-07
期刊：
影响因子：
8.3
通讯作者：
Schaffer CB
中科院分区：
文献类型：
--
作者：
Ahn SJ;Anrather J;Nishimura N;Schaffer CB
补充数字内容可在文本中找到。大脑微出血与认知能力下降有关，但目前尚不清楚它们如何损害神经元功能。在微出血附近通常不会观察到梗死，这表明更微妙的机制，如炎症，可能起作用。由于其体积小且基本上无症状，因此难以在人类和动物模型中实时检测和研究自发性脑微出血。我们通过成年小鼠的慢性颅窗使用体内双光子显微镜观察了直径为100 µm的皮质微出血后的炎症反应，该出血是通过用激光破坏靶向皮质小动脉诱导的。炎症反应包括血液传播的白细胞的侵袭，脑内驻留的小胶质细胞的迁移和增殖，以及星形胶质细胞的活化。几乎所有对微出血作出反应的炎性细胞都是脑内小胶质细胞，但在病变附近也发现了少量的CX 3CR 1+和CCR 2+巨噬细胞，这些巨噬细胞最终来源于血源性单核细胞的侵袭。我们发现了小胶质细胞迁移和增殖的协调模式，其中微出血200 µm内的小胶质细胞在数小时至数天内向病变迁移。与此相反，小胶质细胞的增殖，直到20 - 40小时后的损伤，并主要发生在一个壳状的区域，小胶质细胞的迁移降低了他们的局部密度。这些数据表明，局部小胶质细胞密度变化可能引发增殖。星形胶质细胞在与小胶质细胞相似的区域激活，但延迟了几天。到2周时，这种炎症反应已基本消退。虽然微血管体积很小，但大脑对单次出血的反应是炎症反应，涉及脑驻留细胞和血液来源的细胞，持续数周，并可能影响邻近的大脑微环境。
Supplemental Digital Content is available in the text. Cerebral microbleeds are linked to cognitive decline, but it remains unclear how they impair neuronal function. Infarction is not typically observed near microbleeds, suggesting more subtle mechanisms, such as inflammation, may play a role. Because of their small size and largely asymptomatic nature, real-time detection and study of spontaneous cerebral microbleeds in humans and animal models are difficult. We used in vivo 2-photon microscopy through a chronic cranial window in adult mice to follow the inflammatory response after a cortical microhemorrhage of ≈100 µm diameter, induced by rupturing a targeted cortical arteriole with a laser. The inflammatory response included the invasion of blood-borne leukocytes, the migration and proliferation of brain-resident microglia, and the activation of astrocytes. Nearly all inflammatory cells responding to the microhemorrhage were brain-resident microglia, but a small number of CX3CR1+ and CCR2+ macrophages, ultimately originating from the invasion of blood-borne monocytes, were also found near the lesion. We found a coordinated pattern of microglia migration and proliferation, where microglia within 200 µm of the microhemorrhage migrated toward the lesion over hours to days. In contrast, microglia proliferation was not observed until ≈40 hours after the lesion and occurred primarily in a shell-shaped region where the migration of microglia decreased their local density. These data suggest that local microglia density changes may trigger proliferation. Astrocytes activated in a similar region as microglia but delayed by a few days. By 2 weeks, this inflammatory response had largely resolved. Although microhemorrhages are small in size, the brain responds to a single bleed with an inflammatory response that involves brain-resident and blood-derived cells, persists for weeks, and may impact the adjacent brain microenvironment.