PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury

Journal of Neuroinflammation

Qigui Yu¹  Fahim Syed¹  Wei Li¹  Ping Li²  Fang Yuan³  Xiang Gao³ 

[1] Department of Microbiology and Immunology, Medical Science Building, MS267, Indiana University School of Medicine, 635 Barnhill Drive, 46202, Indianapolis, IN, USA;Department of Surgery, Indiana University School of Medicine, 46202, Indianapolis, IN, USA;Spinal Cord and Brain Injury Research Group, Department of Neurological Surgery, Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W. 15th Street, 46202, Indianapolis, IN, USA;

关键词: Traumatic brain injury;    Astrocyte;    Immune checkpoint;    PD-L1;    Intrinsic signaling;    Neuroimmune response;    Neuroinflammation;   

DOI  :  10.1186/s12974-022-02398-x

来源: Springer

【 摘 要 】

BackgroundTissue 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.MethodsWe 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.ResultsWe 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.ConclusionsPD-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.

【 授权许可】

CC BY