Journal
NEUROSURGERY
Volume 88, Issue 4, Pages 855-863Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/neuros/nyaa495
Keywords
Subarachnoid hemorrhage; Cerebral vasospasm; Programmed death-1; Programmed death ligand-1; Monocyte
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The study aimed to evaluate the role of programmed death-1 (PD-1) in cerebral vasospasm using a mouse model. Results showed that PD-1+ monocytes were identified as mediators of cerebral vasospasm, supporting PD-1 agonism as a novel therapeutic strategy. Human correlative studies confirmed the presence of PD-1+ monocytes in the peripheral blood of patients with ruptured aneurysms.
BACKGROUND: Cerebral vasospasm is a major source of morbidity and mortality following aneurysm rupture and has limited treatment options. OBJECTIVE: To evaluate the role of programmed death-1 (PD-1) in cerebral vasospasm. METHODS: Endovascular internal carotid artery perforation (ICAp) was used to induce cerebral vasospasm in mice. To evaluate the therapeutic potential of targeting PD-1, programmed death ligand-1 (PD-L1) was administered 1 h after ICAp and vasospasm was measured histologically at the level of the ICA bifurcation bilaterally. PD-1 expressing immune cell populations were evaluated by flow cytometry. To correlate these findings to patients and evaluate the potential of PD-1 as a biomarker, monocytes were isolated from the peripheral blood and analyzed by flow cytometry in a cohort of patients with ruptured cerebral aneurysms. The daily frequency of PD-1+ monocytes in the peripheral blood was correlated to transcranial Doppler velocities as well as clinical and radiographic vasospasm. RESULTS: We found that PD-L1 administration prevented cerebral vasospasm by inhibiting ingress of activated Ly6c+ and CCR2+ monocytes into the brain. Human correlative studies confirmed the presence of PD-1+ monocytes in the peripheral blood of patients with ruptured aneurysms and the frequency of these cells corresponded with cerebral blood flow velocities and clinical vasospasm. CONCLUSION: Our results identify PD-1+ monocytes as mediators of cerebral vasospasm and support PD-1 agonism as a novel therapeutic strategy.
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