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

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 Ly6Clo, CD43hi, 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.

Paper: Brain, Behavior, and Immunity. December 7, 2023. | Pubmed