Spinal Cord and Brain Injury Research Group, Department of Neurological Surgery, Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W. 15th Street, Indianapolis, IN, 46202, USA.
Department of Microbiology and Immunology, Medical Science Building, MS267, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA.
J Neuroinflammation. 2022 Feb 8;19(1):43. doi: 10.1186/s12974-022-02398-x.
Tissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain. While appropriate acute and transient neuroimmune and neuroinflammatory responses facilitate the repair and adaptation of injured brain tissues, prolonged and excessive neuroimmune and neuroinflammatory responses exacerbate brain damage. The mechanisms that control the intensity and duration of neuroimmune and neuroinflammatory responses in TBI largely remain elusive.
We used the controlled cortical impact (CCI) model of TBI to study the role of immune checkpoints (ICPs), key regulators of immune homeostasis, in the regulation of neuroimmune and neuroinflammatory responses in the brain in vivo.
We found that de novo expression of PD-L1, a potent inhibitory ICP, was robustly and transiently induced in reactive astrocytes, but not in microglia, neurons, or oligodendrocyte progenitor cells (OPCs). These PD-L1 reactive astrocytes were highly enriched to form a dense zone around the TBI lesion. Blockade of PD-L1 signaling enlarged brain tissue cavity size, increased infiltration of inflammatory Ly-6C monocytes/macrophages (M/Mɸ) but not tissue-repairing Ly-6CF4/80 M/Mɸ, and worsened TBI outcomes in mice. PD-L1 gene knockout enhanced production of CCL2 that is best known for its ability to interact with its cognate receptor CCR2 on Ly-6C M/Mϕ to chemotactically recruit these cells into inflammatory sites. Mechanically, PD-L1 signaling in astrocytes likely exhibits dual inhibitory activities for the prevention of excessive neuroimmune and neuroinflammatory responses to TBI through (1) the PD-1/PD-L1 axis to suppress the activity of brain-infiltrating PD-1 immune cells, such as PD-1 T cells, and (2) PD-L1 intrinsic signaling to regulate the timing and intensity of astrocyte reactions to TBI.
PD-L1 astrocytes act as a gatekeeper to the brain to control TBI-related neuroimmune and neuroinflammatory responses, thereby opening a novel avenue to study the role of ICP-neuroimmune axes in the pathophysiology of TBI and other neurological disorders.
组织损伤和细胞破坏是创伤性脑损伤（TBI）的主要事件，它会在大脑中引发无菌性神经免疫和神经炎症反应。虽然适当的急性和短暂的神经免疫和神经炎症反应有助于受损脑组织的修复和适应，但长期和过度的神经免疫和神经炎症反应会加剧脑损伤。控制 TBI 中神经免疫和神经炎症反应强度和持续时间的机制在很大程度上仍不清楚。
我们使用控制皮质撞击（CCI）TBI 模型来研究免疫检查点（ICPs），即免疫稳态的关键调节剂，在体内调节大脑中神经免疫和神经炎症反应中的作用。
我们发现，PD-L1 的新表达，一种有效的抑制性 ICP，在反应性星形胶质细胞中强烈且短暂地诱导，但不在小胶质细胞、神经元或少突胶质细胞祖细胞（OPC）中诱导。这些 PD-L1 反应性星形胶质细胞高度富集，在 TBI 病变周围形成一个密集区。PD-L1 信号阻断增加了炎症性 Ly-6C 单核细胞/巨噬细胞（M/Mɸ）的浸润，但不增加组织修复性 Ly-6CF4/80 M/Mɸ的浸润，并且在小鼠中加重了 TBI 结局。PD-L1 基因敲除增强了 CCL2 的产生，CCL2 以其与 Ly-6C M/Mϕ上的同源受体 CCR2 相互作用的能力而闻名，能够趋化性地将这些细胞招募到炎症部位。在机制上，星形胶质细胞中的 PD-L1 信号可能通过（1）PD-1/PD-L1 轴抑制大脑浸润的 PD-1 免疫细胞（如 PD-1 T 细胞）的活性，以及（2）PD-L1 内在信号来发挥双重抑制作用，以防止 TBI 引起的过度神经免疫和神经炎症反应，从而调节星形胶质细胞对 TBI 的反应的时间和强度。
PD-L1 星形胶质细胞作为大脑的守门员，控制与 TBI 相关的神经免疫和神经炎症反应，从而为研究 ICP-神经免疫轴在 TBI 和其他神经疾病的病理生理学中的作用开辟了新途径。
