Zhang Jingdong, Gong Xinrui, Xiong Huangui
Department of Pharmacology and Experiment Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Anesthesiology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, China.
Eur J Neurosci. 2021 Mar 16. doi: 10.1111/ejn.15187.
Recent observations indicate that cerebral white matter (WM) exhibits a higher chemoattractant capability for immune cells. The C-C motif chemokine ligands 2 and 3 (CCL2, CCL3) are key chemokines for monocytes and T cells. However, tissue differential of these chemokines is unclear, although the higher CCL2/3 mRNA levels were found in rodent WM. It has been shown that more immune cells infiltrated to WM than to grey matter (GM) in multiple sclerosis (MS) and human/simian immunodeficiency virus (HIV/SIV)-infected brains. More nodular lesions have also been identified in the WM of patients with MS or HIV/SIV encephalitis. We hypothesize that higher levels of CCL2/3 in the WM may associate with neuropathogenesis. To test this hypothesis, we compared CCL2 and CCL3 peptide levels in WM and GM of rat and human, and found both were significantly higher in the WM. Next, we tested the effect of CCL2 on primary rat microglia migration and observed a dose-dependent migratory pattern. Then, we assessed effects of WM and GM homogenates on microglia chemotaxis and observed significant stronger effects of WM than GM in a concentration-dependent manner. The concentration-dependent pattern of tissue homogenates on chemotaxis was similar to the effect of CCL2. Finally, we found the chemoattractant effects of WM on microglia were significantly attenuated by addition of a CCL2 receptor blocker to culture medium and a neutralizing antibody against CCL3 functional motif in the WM homogenate. Taking together, these results suggest that CCL2/3 played significant roles in the microglia chemotaxis toward WM homogenate.
最近的观察结果表明，脑白质（WM）对免疫细胞表现出更高的趋化能力。C-C基序趋化因子配体2和3（CCL2、CCL3）是单核细胞和T细胞的关键趋化因子。然而，尽管在啮齿动物的白质中发现CCL2/3 mRNA水平较高，但这些趋化因子的组织差异尚不清楚。研究表明，在多发性硬化症（MS）以及人类/猿猴免疫缺陷病毒（HIV/SIV）感染的大脑中，浸润到白质的免疫细胞比灰质（GM）更多。在MS或HIV/SIV脑炎患者的白质中也发现了更多的结节性病变。我们推测，白质中较高水平的CCL2/3可能与神经病理发生有关。为了验证这一假设，我们比较了大鼠和人类白质和灰质中CCL2和CCL3肽的水平，发现两者在白质中均显著更高。接下来，我们测试了CCL2对原代大鼠小胶质细胞迁移的影响，并观察到剂量依赖性的迁移模式。然后，我们评估了白质和灰质匀浆对小胶质细胞趋化性的影响，并观察到白质比灰质具有明显更强的浓度依赖性作用。组织匀浆对趋化性的浓度依赖性模式与CCL2的作用相似。最后，我们发现，通过在培养基中添加CCL2受体阻滞剂以及在白质匀浆中添加针对CCL3功能基序的中和抗体，白质对小胶质细胞的趋化作用显著减弱。综上所述，这些结果表明CCL2/3在小胶质细胞向白质匀浆的趋化过程中发挥了重要作用。
