Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke

Jennifer E Kim; Ryan P Lee; Eli Yazigi; Lyla Atta; James Feghali; Ayush Pant; Aanchal Jain; Idan Levitan; Eileen Kim; Kisha Patel; Nivedha Kannapadi; Pavan Shah; Adnan Bibic; Zhipeng Hou; Justin M Caplan; L Fernando Gonzalez; Judy Huang; Risheng Xu; Jean Fan; Betty Tyler; Henry Brem; Vassiliki A Boussiotis; Lauren Jantzie; Shenandoah Robinson; Raymond C Koehler; Michael Lim; Rafael J Tamargo; Christopher M Jackson

doi:10.1016/j.bbi.2023.12.007

Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke

Brain Behav Immun. 2024 Feb:116:160-174. doi: 10.1016/j.bbi.2023.12.007. Epub 2023 Dec 7.

Authors

Jennifer E Kim¹, Ryan P Lee¹, Eli Yazigi¹, Lyla Atta², James Feghali¹, Ayush Pant³, Aanchal Jain¹, Idan Levitan⁴, Eileen Kim¹, Kisha Patel¹, Nivedha Kannapadi¹, Pavan Shah¹, Adnan Bibic⁵, Zhipeng Hou⁶, Justin M Caplan¹, L Fernando Gonzalez¹, Judy Huang¹, Risheng Xu¹, Jean Fan⁷, Betty Tyler¹, Henry Brem¹, Vassiliki A Boussiotis⁸, Lauren Jantzie⁹, Shenandoah Robinson⁹, Raymond C Koehler¹⁰, Michael Lim¹¹, Rafael J Tamargo¹, Christopher M Jackson¹²

Affiliations

¹ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, the United States of America.
² Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, the United States of America; Center for Computational Biology, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, the United States of America; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, the United States of America.
³ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, the United States of America; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, the United States of America.
⁴ Department of Neurosurgery, Rabin Medical Center, Sackler Medical School, Petah Tikva, Israel.
⁵ F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, the United States of America; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, the United States of America.
⁶ Department of Radiology, School of Medicine, Johns Hopkins University, Baltimore, MD, the United States of America.
⁷ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, the United States of America.
⁸ Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, the United States of America.
⁹ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, the United States of America; Departments of Pediatrics, Johns Hopkins University School of Medicine, Maryland, the United States of America; Kennedy Krieger Institute, Maryland, the United States of America; Department of Neurology, Johns Hopkins University School of Medicine, Maryland, the United States of America.
¹⁰ Departments of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, the United States of America.
¹¹ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, the United States of America.
¹² Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, the United States of America. Electronic address: cjacks53@jhmi.edu.

PMID: 38070624
DOI: 10.1016/j.bbi.2023.12.007

Abstract

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6C^lo, CD43^hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.

Keywords: Immune checkpoints; Inflammation; Ischemic stroke; Large vessel occlusion; MCAO; Monocytes; sPD-L1.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
B7-H1 Antigen / metabolism
Brain Edema* / metabolism
Humans
Infarction, Middle Cerebral Artery / metabolism
Ischemic Stroke*
Mice
Monocytes / metabolism
Programmed Cell Death 1 Receptor / metabolism

Substances

Programmed Cell Death 1 Receptor
B7-H1 Antigen