Nguyen Rita H, Newton Michelle, Kratofil Rachel M, Scott Brittney N V, Castanheira Fernanda, Kim Jung-Seok, Ginhoux Florent, Jung Steffen, Kubes Paul
Department of Pharmacology and Physiology, University of Calgary, Calgary T2N1N4, AB, Canada.
Snyder Institute for Chronic Diseases, Cumming School of Medicine, Calgary T2N1N4, AB, Canada.
Proc Natl Acad Sci U S A. 2025 May 27;122(21):e2414316122. doi: 10.1073/pnas.2414316122. Epub 2025 May 19.
Concussions can cause debilitating symptoms despite no evidence of structural changes on diagnostic imaging. The cellular events occurring in the brain parenchyma following concussion, especially repetitive concussion, are not well elucidated. We developed a concussion model to induce a confined area of injury without causing frank hemorrhage. Using intravital microscopy, we observe activation of the vasculature that supported neutrophil rolling and platelet adhesion but no overt cellular recruitment from blood into brain parenchyma. Activated resident, not monocyte-derived, macrophages relocated to the injury site via Cx3cr1 and phagocytosed dysfunctional/detached astrocytes via scavenger receptors and TLR4, particularly after repetitive concussion. Additionally, microglia sealed areas of blood-brain barrier (BBB) disruption via purinergic pathways. Using a splitCre approach to dissect microglia and perivascular macrophages, we show that microglial invasion into the injury site is key to reducing BBB disruption. Our data suggest that microglia repair the BBB following concussion, but in doing so significantly alter the cellular ultrastructure of the brain milieu.
尽管诊断成像未显示结构变化的证据，但脑震荡仍可导致使人衰弱的症状。脑震荡后，尤其是重复性脑震荡后，脑实质中发生的细胞事件尚未得到充分阐明。我们开发了一种脑震荡模型，以诱导一个局限的损伤区域而不引起明显出血。利用活体显微镜，我们观察到支持中性粒细胞滚动和血小板黏附的血管系统激活，但没有明显的细胞从血液募集到脑实质中。活化的驻留巨噬细胞而非单核细胞衍生的巨噬细胞通过Cx3cr1重新定位到损伤部位，并通过清道夫受体和TLR4吞噬功能失调/分离的星形胶质细胞，特别是在重复性脑震荡后。此外，小胶质细胞通过嘌呤能途径封闭血脑屏障（BBB）破坏区域。使用分裂Cre方法剖析小胶质细胞和血管周围巨噬细胞，我们表明小胶质细胞侵入损伤部位是减少BBB破坏的关键。我们的数据表明，小胶质细胞在脑震荡后修复BBB，但在此过程中会显著改变脑微环境的细胞超微结构。
