PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury.
PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury.
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DOI：
10.1186/s12974-022-02398-x
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发表时间：
2022-02-08
影响因子：
9.3
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Gao X;Li W;Syed F;Yuan F;Li P;Yu Q
组织损伤和细胞破坏是创伤性脑损伤（TBI）的主要事件，其触发脑内无菌的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促进了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加剧了脑损伤。控制TBI中神经免疫和神经炎症反应的强度和持续时间的机制在很大程度上仍然难以捉摸。我们使用TBI的受控皮质撞击（CCI）模型来研究免疫检查点（ICP），免疫稳态的关键调节因子，在体内脑中神经免疫和神经炎症反应的调节中的作用。我们发现，PD-L1（一种有效的抑制性ICP）的从头表达在反应性星形胶质细胞中被强烈且短暂地诱导，但在小胶质细胞、神经元或少突胶质细胞祖细胞（OPCs）中没有。这些PD-L1+反应性星形胶质细胞高度富集，在TBI病变周围形成致密区。PD-L1信号传导的阻断扩大了脑组织腔的大小，增加了炎性Ly-6C高单核细胞/巨噬细胞（M/M+）的浸润，但没有组织修复性Ly-6C低F4/80+ M/M+，并使小鼠的TBI结果恶化。PD-L1基因敲除增强了CCL 2的产生，CCL 2因其与Ly-6C高M/M受体上的同源受体CCR 2相互作用的能力而闻名，从而通过化学作用将这些细胞招募到炎症部位。从机制上讲，星形胶质细胞中的PD-L1信号传导可能表现出双重抑制活性，通过（1）PD-1/PD-L1轴抑制脑浸润PD-1+免疫细胞（如PD-1+ T细胞）的活性，以及（2）PD-L1内在信号传导调节星形胶质细胞对TBI反应的时间和强度，来预防对TBI的过度神经免疫和神经炎症反应。PD-L1+星形胶质细胞作为大脑的守门人，控制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和其他神经系统疾病的病理生理学中的作用开辟了一条新途径。在线版本包含补充材料，可通过10.1186/s12974-022-02398-x获得。
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-6CHigh monocytes/macrophages (M/Mɸ) but not tissue-repairing Ly-6CLowF4/80+ 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-6CHigh 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. The online version contains supplementary material available at 10.1186/s12974-022-02398-x.
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T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
5.3
作者：
Burda JE;Bernstein AM;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
16.2
作者：
Burda JE;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
8.8
作者：
Gato-Canas, Maria;Zuazo, Miren;Escors, David
通讯作者：
Escors, David