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

Xiang Gao,Qigui Yu,Fang Yuan,Fahim Syed,Wei Li,Ping Li

doi:10.1186/s12974-022-02398-x

Abstract

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.

Highlights

Tissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain
We found that de novo expression of Programmed death-ligand 1 (PD-L1), a key inhibitory Immune checkpoint (ICP) that exerts dual inhibitory signals to suppress the activity of Programmed cell death protein 1 (PD-1)+ T cells via the PD-1/PD-L1 axis and the function of PD-L1+ cells via a novel intrinsic signaling, was robustly and induced in astrocytes that were positive for Glial fibrillary acidic protein (GFAP), a reactive astrocyte marker
We used TBI mice to explore whether ICP expression could be induced or regulated in the brain in vivo in response to neuroimmune activation, as a sterile immune response develops within minutes in TBI

Summary

Introduction

Tissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain. Primary injury refers to the initial direct impact that causes focal and diffuse damage of the brain. The secondary injury of TBI develops in minutes to hours following the initial primary injury and contributes to further damage of brain tissue [3, 5, 6]. Secondary injury remains an important determinant of TBI outcome, as a large percentage of people with TBI develop neurological function deficits days to weeks after the event. The exact roles of the neuroimmune and neuroinflammatory responses in the physiological and pathological processes of secondary injury are largely unknown

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