Transiently proliferating perivascular microglia harbor M1 type and precede cerebrovascular changes in a chronic hypertension model
Transiently proliferating perivascular microglia harbor M1 type and precede cerebrovascular changes in a chronic hypertension model
复制标题
DOI：
10.1186/s12974-019-1467-7
复制
发表时间：
2019-04-10
影响因子：
9.3
通讯作者：
Mizuno, Toshiki
中科院分区：
文献类型：
--
作者：
Koizumi, Takashi;Taguchi, Katsutoshi;Mizuno, Toshiki
背景：小胶质细胞在维持大脑稳态中发挥着至关重要的作用。激活的小胶质细胞表现出双相影响，分别通过 M2 和 M1 小胶质细胞促进有益修复并造成有害损伤。众所周知，小胶质细胞最初被激活至 M2 状态，随后切换至 M1 状态，在急性缺血模型中称为 M2 至 M1 类别转换。然而，慢性和散发性高血压中小胶质细胞的激活过程仍然知之甚少。我们的目的是使用慢性高血压模型，即醋酸脱氧皮质酮（DOCA）盐治疗的 Wistar 大鼠来阐明这一过程。方法：单侧肾切除术后，将大鼠随机分为 DOCA 盐组、安慰剂组和对照组。 DOCA-盐大鼠每周皮下注射DOCA（40 mg/kg），并持续提供1% NaCl的饮用水。安慰剂大鼠每周皮下注射媒介物并提供自来水。对照大鼠未接受 DOCA 或 NaCl 给药。为了研究小胶质细胞 M1 和 M2 特异性标记物的时间表达谱，在 DOCA 盐治疗 2、3 或 4 周后对动物进行免疫组织化学和生化研究。 结果：DOCA 和盐给药 2 周后，观察到与血管并列的圆形小胶质细胞，突起稍短，尽管组织病理学结果正常，但发生了高血压。 DOCA和盐给药3周后，M1状态的血管周围和实质小胶质细胞显着增加，此时开始观察到局部组织病理学发现，但没有发生脑血管破坏。另一方面，此时血管周围从未观察到 M2 状态的小胶质细胞。有趣的是，在 M1 激活之前，约 55% 的血管周围小胶质细胞短暂表达细胞增殖标志物之一的 Ki-67。结论：我们得出结论，在 DOCA 盐大鼠中，静息的血管周围小胶质细胞通过短暂的增殖状态直接转变为促炎 M1 状态。我们的结果表明，慢性高血压中小胶质细胞的激活机制与急性缺血模型不同。增殖性小胶质细胞可能是高血压引起的脑血管损伤发展的最初关键参与者。小胶质细胞增殖和激活的微调可能构成一种创新的治疗策略来阻止其发展。
Background: Microglia play crucial roles in the maintenance of brain homeostasis. Activated microglia show a biphasic influence, promoting beneficial repair and causing harmful damage via M2 and M1 microglia, respectively. It is well-known that microglia are initially activated to the M2 state and subsequently switch to the M1 state, called M2-to-M1 class switching in acute ischemic models. However, the activation process of microglia in chronic and sporadic hypertension remains poorly understood. We aimed to clarify the process using a chronic hypertension model, the deoxycorticosterone acetate (DOCA)-salt-treated Wistar rats.Methods: After unilateral nephrectomy, the rats were randomly divided into DOCA-salt, placebo, and control groups. DOCA-salt rats received a weekly subcutaneous injection of DOCA (40 mg/kg) and were continuously provided with 1% NaCl in drinking water. Placebo rats received a weekly subcutaneous injection of vehicle and were provided with tap water. Control rats received no administration of DOCA or NaCl. To investigate the temporal expression profiles of M1- and M2-specific markers for microglia, the animals were subjected to the immunohistochemical and biochemical studies after 2, 3, or 4 weeks DOCA-salt treatment.Results: Hypertension occurred after 2 weeks of DOCA and salt administration, when round-shaped microglia with slightly shortened processes were observed juxtaposed to the vessels, although the histopathological findings were normal. After 3 weeks of DOCA and salt administration, M1-state perivascular and parenchyma microglia significantly increased, when local histopathological findings began to be observed but cerebrovascular destruction did not occur. On the other hand, M2-state microglia were never observed around the vessels at this period. Interestingly, prior to M1 activation, about 55% of perivascular microglia transiently expressed Ki-67, one of the cell proliferation markers.Conclusions: We concluded that the resting perivascular microglia directly switched to the pro-inflammatory M1 state via a transient proliferative state in DOCA-salt rats. Our results suggest that the activation machinery of microglia in chronic hypertension differs from acute ischemic models. Proliferative microglia are possible initial key players in the development of hypertension-induced cerebral vessel damage. Fine-tuning of microglia proliferation and activation could constitute an innovative therapeutic strategy to prevent its development.