Programmed death-1 pathway limits central nervous system inflammation and neurologic deficits in murine experimental stroke

Xuefang Ren, Kozaburo Akiyoshi, Arthur A. Vandenbark, Patricia D. Hurn, Halina Offner

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background and Purpose-Evaluation of infarct volumes and infiltrating immune cell populations in mice after middle cerebral artery occlusion strongly implicates a mixture of both pathogenic and regulatory immune cell subsets that affect stroke outcome. Our goal was to evaluate the contribution of the well-described coinhibitory pathway, programmed death (PD)-1, to the development of middle cerebral artery occlusion. Methods-Infarct volumes, functional outcomes, and effects on infiltrating immune cell populations were compared in wild-type C57BL/6 versus PD-1-deficient mice after 60 minutes middle cerebral artery occlusion and 96 hours reperfusion. Results-The results clearly demonstrate a previously unrecognized activity of the PD-1 pathway to limit infarct volume, recruitment of inflammatory cells from the periphery, activation of macrophages and central nervous system microglia, and functional neurological deficits. These regulatory functions were associated with increased percentages of circulating PD-ligand-1 and PD-ligand-2 expressing CD19 + B-cells in blood, the spleen, and central nervous system with the capacity to inhibit activation of inflammatory T-cells and central nervous system macrophages and microglial cells through upregulated PD-1. Conclusions-Our novel observations are the first to implicate PD-1 signaling as a major protective pathway for limiting central nervous system inflammation in middle cerebral artery occlusion. This inhibitory circuit would likely be pivotal in reducing stroke-associated Toll-like receptor-2-and Toll like receptor-4-mediated release of neurotoxic factors by activated central nervous system microglia.

Original languageEnglish
Pages (from-to)2578-2583
Number of pages6
JournalStroke
Volume42
Issue number9
DOIs
Publication statusPublished - Sep 1 2011

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialised Nursing

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