Microglial depletion abolishes ischemic preconditioning in white matter.
Microglial depletion abolishes ischemic preconditioning in white matter.
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作者：
Hamner MA;McDonough A;Gong DC;Todd LJ;Rojas G;Hodecker S;Ransom CB;Reh TA;Ransom BR;Weinstein JR
缺血预处理（IPC）是一种短暂的、非损伤性的缺血暴露增强对随后缺血挑战的耐受的现象。IPC的机制主要在啮齿动物中风模型中研究，其中灰质（GM）占大脑的约85%。在人类中，白色物质（WM）占大脑体积的50%，是中风损伤的关键组成部分。我们利用小鼠视神经（MON）建立了一种新的CNS WM IPC模型，并鉴定了所涉及的免疫信号通路。在这里，我们测试的假设，小胶质细胞是必要的WM IPC。通过用殖民地-1（CSFR 1）抑制剂PLX 5622处理使小胶质细胞耗竭。MONS在体内暴露于短暂缺血，72小时后急性分离，并进行氧-葡萄糖剥夺（OGD）以模拟严重的缺血性损伤（即中风）。通过记录复合动作电位（CAPs）和使用定量体视学显微镜检查评估功能和结构轴突恢复。小胶质细胞耗竭消除IPC介导的保护。在对照小鼠中，与非预处理的MONS相比，在预处理的MONS中CAP恢复得到改善，然而，在PLX 5622处理的小鼠中，我们观察到预处理和非预处理的MONS之间的CAP恢复没有差异。小胶质细胞耗竭也取消IPC的轴突完整性和生存的成熟（APC+）少突胶质细胞OGD后的保护作用。IPC介导的保护是独立的视网膜损伤，这表明它是由缺血暴露的WM内在的机械过程的结果。我们的结论是，预处理的小胶质细胞是至关重要的IPC在WM。“预处理小胶质细胞”表型可能会防止其他中枢神经系统病变，是一个值得探索的神经治疗视野。
Ischemic preconditioning (IPC) is a phenomenon whereby a brief, non-injurious ischemic exposure enhances tolerance to a subsequent ischemic challenge. The mechanism of IPC has mainly been studied in rodent stroke models where gray matter (GM) constitutes about 85% of the cerebrum. In humans, white matter (WM) is 50% of cerebral volume and is a critical component of stroke damage. We developed a novel CNS WM IPC model using the mouse optic nerve (MON) and identified the involved immune signaling pathways. Here we tested the hypothesis that microglia are necessary for WM IPC. Microglia were depleted by treatment with the colony stimulating factor receptor-1 (CSFR1) inhibitor PLX5622. MONs were exposed to transient ischemia in vivo, acutely isolated 72 hours later, and subjected to oxygen-glucose deprivation (OGD) to simulate a severe ischemic injury (i.e. stroke). Functional and structural axonal recovery was assessed by recording compound action potentials (CAPs) and by microscopy using quantitative stereology. Microglial depletion eliminated IPC-mediated protection. In control mice, CAP recovery was improved in preconditioned MONs compared with non-preconditioned MONs, however, in PLX5622-treated mice, we observed no difference in CAP recovery between preconditioned and non-preconditioned MONs. Microglial depletion also abolished IPC protective effects on axonal integrity and survival of mature (APC+) oligodendrocytes after OGD. IPC-mediated protection was independent of retinal injury suggesting it results from mechanistic processes intrinsic to ischemia-exposed WM. We conclude that preconditioned microglia are critical for IPC in WM. The ‘preconditioned microglia’ phenotype might protect against other CNS pathologies and is a neurotherapeutic horizon worth exploring.
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DOI：
10.1073/pnas.1922788117
发表时间：
2020-09-22
影响因子：
11.1
作者：
Lei F;Cui N;Zhou C;Chodosh J;Vavvas DG;Paschalis EI
通讯作者：
Paschalis EI
影响因子：
5.3
作者：
Baltan, Selva;Besancon, Elaine F.;Ransom, Bruce R.
通讯作者：
Ransom, Bruce R.
影响因子：
5.3
作者：
Hilla, Alexander M.;Diekmann, Heike;Fischer, Dietmar
通讯作者：
Fischer, Dietmar
影响因子：
3.3
作者：
LAWSON, LJ;PERRY, VH;GORDON, S
通讯作者：
GORDON, S
影响因子：
4.4
作者：
Kashiwagi, K;Ou, B;Tsukahara, S
通讯作者：
Tsukahara, S