Department of Neurosurgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
Front Immunol. 2023 Feb 17;14:1105973. doi: 10.3389/fimmu.2023.1105973. eCollection 2023.
Balancing microglia M1/M2 polarization is an effective therapeutic strategy for neuroinflammation after subarachnoid hemorrhage (SAH). Pleckstrin homology-like domain family A member 1 (PHLDA1) has been demonstrated to play a crucial role in immune response. However, the function roles of PHLDA1 in neuroinflammation and microglial polarization after SAH remain unclear. In this study, SAH mouse models were assigned to treat with scramble or PHLDA1 small interfering RNAs (siRNAs). We observed that PHLDA1 was significantly increased and mainly distributed in microglia after SAH. Concomitant with PHLDA1 activation, nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome expression in microglia was also evidently enhanced after SAH. In addition, PHLDA1 siRNA treatment significantly reduced microglia-mediated neuroinflammation by inhibiting M1 microglia and promoting M2 microglia polarization. Meanwhile, PHLDA1 deficiency reduced neuronal apoptosis and improved neurological outcomes after SAH. Further investigation revealed that PHLDA1 blockade suppressed the NLRP3 inflammasome signaling after SAH. In contrast, NLRP3 inflammasome activator nigericin abated the beneficial effects of PHLDA1 deficiency against SAH by promoting microglial polarization to M1 phenotype. In all, we proposed that PHLDA1 blockade might ameliorate SAH-induced brain injury by balancing microglia M1/M2 polarization suppression of NLRP3 inflammasome signaling. Targeting PHLDA1 might be a feasible strategy for treating SAH.
平衡小胶质细胞 M1/M2 极化是蛛网膜下腔出血 (SAH) 后神经炎症的有效治疗策略。磷酯酶同源结构域家族 A 成员 1 (PHLDA1) 已被证明在免疫反应中发挥关键作用。然而，PHLDA1 在 SAH 后神经炎症和小胶质细胞极化中的功能作用尚不清楚。在这项研究中，将 SAH 小鼠模型分为 scramble 或 PHLDA1 小干扰 RNA (siRNA) 治疗组。我们观察到，SAH 后 PHLDA1 显著增加，主要分布在小胶质细胞中。与 PHLDA1 激活同时，SAH 后小胶质细胞中 NOD 样受体含 pyrin 结构域蛋白 3 (NLRP3) 炎性体的表达也明显增强。此外，PHLDA1 siRNA 治疗通过抑制 M1 小胶质细胞和促进 M2 小胶质细胞极化，显著减轻小胶质细胞介导的神经炎症。同时，PHLDA1 缺失减少 SAH 后的神经元凋亡并改善神经功能预后。进一步研究表明，PHLDA1 阻断抑制了 SAH 后的 NLRP3 炎性体信号。相比之下，NLRP3 炎性体激活剂虎杖苷通过促进小胶质细胞向 M1 表型极化，减弱了 PHLDA1 缺失对 SAH 的有益作用。总之，我们提出 PHLDA1 阻断可能通过平衡小胶质细胞 M1/M2 极化抑制 NLRP3 炎性体信号来改善 SAH 引起的脑损伤。靶向 PHLDA1 可能是治疗 SAH 的一种可行策略。
