NLRP3 Is Involved in the Maintenance of Cerebral Pericytes
NLRP3 Is Involved in the Maintenance of Cerebral Pericytes
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NLRP3 参与大脑周细胞的维护
DOI：
10.3389/fncel.2020.00276
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发表时间：
2020-08-21
影响因子：
5.3
通讯作者：
Liu, Yang
中科院分区：
文献类型：
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作者：
Quan, Wenqiang;Luo, Qinghua;Liu, Yang
周细胞在调节脑内毛细血管的结构和功能方面起着核心作用。然而，驱动周细胞增殖和分化的分子机制尚不清楚。在我们的研究中，我们对NACHT、LRR和PYD结构域包含蛋白3(NLRP3)缺陷的和野生型窝仔小鼠进行了免疫染色，观察到NLRP3缺乏减少了脑组织中血小板衍生生长因子受体β(PDGFRβ)阳性的周细胞和IV型胶原免疫反应血管。在Western印迹分析中，NLRP3基因缺陷小鼠脑内分离的微血管中PDGFRCD13和β蛋白表达减少。我们进一步用NLRP3抑制剂MCC950处理培养的周细胞，发现抑制NLRP3可以抑制细胞的增殖，但不能诱导细胞凋亡。抑制NLRP3还可降低培养的周细胞中PDGFRCD13和β的蛋白水平。相反，含有NLRP3的炎症体的主要产物IL-1β处理后，培养细胞中PDGFRβ和CD13的蛋白水平增加。血小板衍生生长因子受体β和CD13蛋白水平的改变与AKT的磷酸化有关。抑制AKT可降低这两种蛋白标记物，并取消IL-1β激活的作用。因此，NLRP3的激活可能是通过磷酸化AKT来维持健康大脑中的周细胞的必不可少的。在NLRP3抑制剂的临床治疗中应考虑对脑血管周细胞的潜在不良影响。
Pericytes play a central role in regulating the structure and function of capillaries in the brain. However, molecular mechanisms that drive pericyte proliferation and differentiation are unclear. In our study, we immunostained NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-deficient and wild-type littermate mice and observed that NLRP3 deficiency reduced platelet-derived growth factor receptor β (PDGFRβ)-positive pericytes and collagen type IV immunoreactive vasculature in the brain. In Western blot analysis, PDGFRβ and CD13 proteins in isolated cerebral microvessels from the NLRP3-deficient mouse brain were decreased. We further treated cultured pericytes with NLRP3 inhibitor, MCC950, and demonstrated that NLRP3 inhibition attenuated cell proliferation but did not induce apoptosis. NLRP3 inhibition also decreased protein levels of PDGFRβ and CD13 in cultured pericytes. On the contrary, treatments with IL-1β, the major product of NLRP3-contained inflammasome, increased protein levels of PDGFRβ, and CD13 in cultured cells. The alteration of PDGFRβ and CD13 protein levels were correlated with the phosphorylation of AKT. Inhibition of AKT reduced both protein markers and abolished the effect of IL-1β activation in cultured pericytes. Thus, NLRP3 activation might be essential to maintain pericytes in the healthy brain through phosphorylating AKT. The potential adverse effects on the cerebral vascular pericytes should be considered in clinical therapies with NLRP3 inhibitors.