PD-1+ Monocytes Mediate Cerebral Vasospasm Following Subarachnoid Hemorrhage.

Abstract

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.

• Authors: Christopher M Jackson, John Choi, Denis Routkevitch, Ayush Pant, Laura Saleh, Xiaobu Ye, Justin M Caplan, Judy Huang, Cameron G McDougall, Drew M Pardoll, Henry Brem, Rafael J Tamargo, Michael Lim
• Journal: Neurosurgery (Neurosurgery) Vol. 88 Issue 4 Pg. 855-863 (03 15 2021) ISSN: 1524-4040 [Electronic] United States
• PMID: 33370819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Congress of Neurological Surgeons 2020.

Chemical References

• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor

Topics

• Animals
• Brain (blood supply, diagnostic imaging, drug effects)
• Cerebrovascular Circulation (drug effects, physiology)
• Cohort Studies
• Mice
• Mice, Inbred C57BL
• Monocytes (drug effects, metabolism)
• Programmed Cell Death 1 Receptor (administration & dosage)
• Subarachnoid Hemorrhage (blood, diagnostic imaging, drug therapy)
• Ultrasonography, Doppler, Transcranial (methods)
• Vasospasm, Intracranial (blood, diagnostic imaging, prevention & control)