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

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Enteric Glial Cells in Immunological Disorders of the Gut

“…Also, recent studies reported that EGCs would display inhibitory effects on the proliferation and activity of CD8+ T cells (Kermarrec et al, 2016 ). Though the mechanism underlying such crosstalk between EGCs and CD8+ T cells remains to be fully elucidated, it has been suggested that EGCs may express the checkpoint blockage protein such as PD-L1, similar to that observed in astrocytes of the central nervous system (Gao et al, 2022 ). In addition, it appears a possibility that EGCs might influence the B cell-mediated immunity, as EGCs are present in Peyer’s patches (Biskou et al, 2022 ).…”

PD-1/PD-L Axis in Neuroinflammation: New Insights

“…Accordingly, Lipp et al showed an upregulation of PD-L1 on hippocampal astrocytes in a model of axonal degeneration ( 76 ), suggesting a potential role in the inhibition of T cells. Gao et al described the formation of dense areas of activated astrocytes expressing PD-L1 near the lesions in a traumatic brain injury model ( 42 ). In this model, astrocytes acted as gatekeepers, by blocking the infiltration of inflammatory Ly6c hi monocytes/macrophages, but not the entrance of tissue repairing Ly6c low F4/80 ( 42 ) cells.…”

“…Gao et al described the formation of dense areas of activated astrocytes expressing PD-L1 near the lesions in a traumatic brain injury model ( 42 ). In this model, astrocytes acted as gatekeepers, by blocking the infiltration of inflammatory Ly6c hi monocytes/macrophages, but not the entrance of tissue repairing Ly6c low F4/80 ( 42 ) cells.…”

Targetability of the neurovascular unit in inflammatory diseases of the central nervous system

“…Since astrocytes are highly responsive to immune stimuli, they have the ability to upregulate a wide array of chemokines and adhesion molecules that can serve as an immunologic barrier to prevent excessive influx of inflammatory cells during a CNS insult (Figure 2). 120,123 Interestingly, in the event immune cells breach the BBB, enter the perivascular space, and cross astrocyte endfeet into the parenchyma, astrocytes can express immune checkpoint molecules, or inhibitory receptors, which can induce exhaustion and death of leukocytes, 124,125 providing the CNS multiple layers of immunologic protection. As an example, astrocytes are known to upregulate the immune checkpoint protein programmed death ligand 1 (PD‐L1) in response to inflammatory cytokines, primarily interferons 126 .…”