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Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke.
- Source :
-
Brain, Behavior & Immunity . Feb2024, Vol. 116, p160-174. 15p. - Publication Year :
- 2024
-
Abstract
- • Activation of the innate immune system drives outcomes after stroke. • PD-1+ monocytes in the blood of stroke patients correlate with cerebral edema. • PD-L1 administration decreases edema, improves survival, and promotes recovery. • Myeloid-specific PD-1 knockout abrogates the PD-L1 treatment effect. • PD-1 signaling skews blood monocytes away from an inflammatory phenotype prior to tissue infiltration. 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08891591
- Volume :
- 116
- Database :
- Academic Search Index
- Journal :
- Brain, Behavior & Immunity
- Publication Type :
- Academic Journal
- Accession number :
- 174841463
- Full Text :
- https://doi.org/10.1016/j.bbi.2023.12.007