Traumatic brain injury is a leading cause of morbidity and mortality in adults and children in developed nations. Following the primary injury, microglia, the resident innate immune cells of the CNS, initiate several inflammatory signaling cascades and pathophysiological responses that may persist chronically; chronic neuroinflammation following TBI has been closely linked to the development of neurodegeneration and neurological dysfunction. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that have been shown to regulate several key mechanisms in the inflammatory response to TBI. Increasing evidence has shown that the modulation of the PI3K/AKT signaling pathway has the potential to influence the cellular response to inflammatory stimuli. However, directly targeting PI3K signaling poses several challenges due to its regulatory role in several cell survival pathways. We have previously identified that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), the major negative regulator of PI3K/AKT signaling, is dysregulated following exposure to repetitive mild traumatic brain injury (r-mTBI). Moreover, this dysregulated PI3K/AKT signaling was correlated with chronic microglial-mediated neuroinflammation. Therefore, we interrogated microglial-specific PTEN as a therapeutic target in TBI by generating a microglial-specific, Tamoxifen inducible conditional PTEN knockout model using a CX3CR1 Cre recombinase mouse line PTEN^fl/fl/CX3CR1^+/CreERT2 (mcg-PTEN^cKO), and exposed them to our 20-hit r-mTBI paradigm. Animals were treated with tamoxifen at 76 days post-last injury, and the effects of microglia PTEN deletion on immune-inflammatory responses were assessed at 90-days post last injury. We observed that the deletion of microglial PTEN ameliorated the proinflammatory response to repetitive brain trauma, not only reducing chronic microglial activation and proinflammatory cytokine production but also rescuing TBI-induced reactive astrogliosis, demonstrating that these effects extended beyond microglia alone. Additionally, we observed that the pharmacological inhibition of PTEN with BpV(HOpic) ameliorated the LPS-induced activation of microglial NFκB signaling in vitro. Together, these data provide support for the role of PTEN as a regulator of chronic neuroinflammation following repetitive mild TBI.

创伤性脑损伤是发达国家成人和儿童发病率和死亡率的主要原因。原发性损伤后，小胶质细胞（中枢神经系统的先天性免疫细胞）会启动多种炎症信号级联反应和可能长期持续的病理生理反应；TBI 后的慢性神经炎症与神经变性的发展密切相关和神经功能障碍。磷酸肌醇 3-激酶 (PI3K) 是一个脂质激酶家族，已被证明可调节 TBI 炎症反应中的几个关键机制。越来越多的证据表明，PI3K/AKT 信号通路的调节有可能影响细胞对炎症刺激的反应。然而，由于 PI3K 信号通路在多种细胞存活途径中的调节作用，直接靶向 PI3K 信号通路存在一些挑战。我们之前已经确定磷酸酶和张力蛋白10 号染色体上缺失的同源物 (PTEN) 是 PI3K/AKT 信号的主要负调节因子，在暴露于重复性轻度创伤性脑损伤 (r-mTBI) 后失调。此外，这种失调的 PI3K/AKT 信号与慢性小胶质细胞介导的神经炎症相关。因此，我们通过使用 CX3CR1 Cre重组酶小鼠系 PTEN fl ^/fl/CX3CR1^+/CreERT2(mcg-PTEN^cKO), 并将它们暴露于我们的 20 次命中 r-mTBI 范式。动物在最后一次受伤后 76 天接受他莫昔芬治疗，并在最后一次受伤后 90 天评估小胶质细胞 PTEN 缺失对免疫炎症反应的影响。我们观察到小胶质细胞 PTEN 的缺失改善了对重复性脑外伤的促炎反应，不仅减少了慢性小胶质细胞激活和促炎细胞因子的产生，而且还挽救了 TBI 诱导的反应性星形胶质细胞增生，证明这些作用不仅仅局限于小胶质细胞。此外，我们观察到 BpV(HOpic) 对 PTEN 的药理学抑制改善了 LPS 诱导的小胶质细胞 NFκB 信号通路的体外激活. 总之，这些数据支持 PTEN 作为重复性轻度 TBI 后慢性神经炎症调节剂的作用。