Institute of Neurosciences, the Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, China.
Neurotherapeutics. 2014 Jul;11(3):636-50. doi: 10.1007/s13311-013-0254-x.
The inflammatory response following spinal cord injury (SCI) involves the activation of resident microglia and the infiltration of macrophages. Macrophages and microglia can be polarized into the classically activated proinflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype. Programmed cell death 1 (PD-1) is a critical immune inhibitory receptor involved in innate and adaptive immune responses. However, whether PD-1 is involved in the modulation of macrophage/microglial polarization is unknown. In this study, the mRNA levels of pd1 gradually increased after SCI, and PD-1 protein was found in macrophages/microglia in injured spinal cord sections. PD-1 knockout (KO) mice showed poor locomotor recovery after spinal cord crushing compared with wild-type mice. M1-type macrophages/microglia accumulated in greater numbers in the injured spinal cord of PD-1-KO mice. Under polarized stimulation, induced expression of PD-1 occurred in cultured macrophages and microglia. PD-1 suppressed M1 polarization by reducing the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and promoted M2 polarization by increasing STAT6 phosphorylation. In PD-1-KO mice, the M1 response was enhanced via the activation of STAT1 and nuclear factor-kappa B. Furthermore, PD-1 played various roles in phagocytosis in macrophages and microglia. Therefore, our results suggest that PD-1 signaling plays an important role in the regulation of macrophage/microglial polarization. Thus, deregulated PD-1 signaling may induce the polarization of macrophages/microglia toward the M1 phenotype. Overall, our results provide new insights into the modulatory mechanisms of macrophage/microglial polarization, thereby possibly facilitating the development of new therapies for SCI via the regulation of macrophage/microglial polarization through PD-1 signaling.
脊髓损伤 (SCI) 后的炎症反应涉及驻留小胶质细胞的激活和巨噬细胞的浸润。巨噬细胞和小胶质细胞可以极化为经典激活的促炎 M1 表型或替代激活的抗炎 M2 表型。程序性细胞死亡蛋白 1 (PD-1) 是一种参与先天和适应性免疫反应的关键免疫抑制受体。然而，PD-1 是否参与调节巨噬细胞/小胶质细胞极化尚不清楚。在这项研究中，SCI 后 pd1 的 mRNA 水平逐渐升高，并且在损伤的脊髓切片中发现 PD-1 蛋白存在于巨噬细胞/小胶质细胞中。与野生型小鼠相比，脊髓挤压后 PD-1 敲除 (KO) 小鼠的运动功能恢复较差。在 PD-1-KO 小鼠的损伤脊髓中，M1 型巨噬细胞/小胶质细胞积聚更多。在极化刺激下，培养的巨噬细胞和小胶质细胞中诱导表达 PD-1。PD-1 通过降低信号转导和转录激活因子 1 (STAT1) 的磷酸化来抑制 M1 极化，并通过增加 STAT6 磷酸化来促进 M2 极化。在 PD-1-KO 小鼠中，通过激活 STAT1 和核因子-κB 增强了 M1 反应。此外，PD-1 在巨噬细胞和小胶质细胞的吞噬作用中发挥多种作用。因此，我们的结果表明 PD-1 信号在调节巨噬细胞/小胶质细胞极化中起重要作用。因此，PD-1 信号的失调可能导致巨噬细胞/小胶质细胞向 M1 表型极化。总的来说，我们的结果为巨噬细胞/小胶质细胞极化的调节机制提供了新的见解，从而可能通过 PD-1 信号调节巨噬细胞/小胶质细胞极化来促进 SCI 的新疗法的发展。
