Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kamigyo-ku, Kyoto, 602-8566, Japan.
Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
J Neuroinflammation. 2019 Apr 10;16(1):79. doi: 10.1186/s12974-019-1467-7.
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.
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.
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.
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.
小胶质细胞在维持脑内环境平衡方面发挥着关键作用。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的修复和造成有害的损伤。众所周知，小胶质细胞最初被激活到 M2 状态，随后切换到 M1 状态，在急性缺血模型中称为 M2 到 M1 类转换。然而，慢性和散发性高血压中小胶质细胞的激活过程仍知之甚少。我们旨在使用慢性高血压模型（脱氧皮质酮醋酸盐（DOCA）-盐处理的 Wistar 大鼠）阐明这一过程。
单侧肾切除术后，大鼠被随机分为 DOCA-盐、安慰剂和对照组。DOCA-盐组每周接受一次 DOCA（40mg/kg）皮下注射，并持续给予 1%NaCl 饮用水。安慰剂组每周接受一次载体皮下注射，并给予自来水。对照组大鼠不给予 DOCA 或 NaCl 处理。为了研究 M1 和 M2 特异性小胶质细胞标志物的时间表达谱，在 DOCA-盐处理 2、3 或 4 周后，对动物进行免疫组织化学和生化研究。
DOCA 和盐给药 2 周后发生高血压，此时观察到与血管相邻的圆形小胶质细胞，其突起略有缩短，尽管组织病理学发现正常。DOCA 和盐给药 3 周后，血管周围和实质内 M1 状态的小胶质细胞显著增加，此时开始出现局部组织病理学发现，但脑血管破坏尚未发生。另一方面，在这个时期，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 Ki-67。
我们得出结论，在 DOCA-盐大鼠中，静止的血管周围小胶质细胞通过短暂的增殖状态直接转换为促炎的 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诱导的脑血管损伤发展的最初关键参与者。精细调节小胶质细胞的增殖和激活可能构成一种预防其发展的创新治疗策略。
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