PD-L1 enhances CNS inflammation and infarct volume following experimental stroke in mice in opposition to PD-1

Sheetal Bodhankar, Yingxin Chen, Arthur Vandenbark, Stephanie J. Murphy, Halina Offner

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background: Stroke severity is worsened by recruitment of inflammatory immune cells into the brain. This process depends in part on T cell activation, in which the B7 family of co-stimulatory molecules plays a pivotal role. Previous studies demonstrated more severe infarcts in mice lacking programmed death-1 (PD-1), a member of the B7 family, thus implicating PD-1 as a key factor in limiting stroke severity. The purpose of this study was to determine if this protective effect of PD-1 involves either of its ligands, PD-L1 or PD-L2.Methods: Central nervous system (CNS) inflammation and infarct volume were evaluated in male PD-L1 and PD-L2 knockout (-/-) mice undergoing 60 minutes of middle cerebral artery occlusion (MCAO) followed by 96 hours of reperfusion and compared to wild-type (WT) C57BL/6J mice.Results: PD-L1-/- and PD-L2-/- mice had smaller total infarct volumes compared to WT mice. The PD-L1-/- and to a lesser extent PD-L2-/- mice had reduced levels of proinflammatory activated microglia and/or infiltrating monocytes and CD4+ T cells in the ischemic hemispheres. There was a reduction in ischemia-related splenic atrophy accompanied by lower activation status of splenic T cells and monocytes in the absence of PD-L1, suggesting a pathogenic rather than a regulatory role for both PD-1 ligands (PD-Ls). Suppressor T cells (IL-10-producing CD8+CD122+ T cells) trafficked to the brain in PD-L1-/- mice and there was decreased expression of CD80 on splenic antigen-presenting cells (APCs) as compared to the WT and PD-L2-/- mice.Conclusions: Our novel observations are the first to implicate PD-L1 involvement in worsening outcome of experimental stroke. The presence of suppressor T cells in the right MCAO-inflicted hemisphere in mice lacking PD-L1 implicates these cells as possible key contributors for controlling adverse effects of ischemia. Increased expression of CD80 on APCs in WT and PD-L2-/- mice suggests an overriding interaction leading to T cell activation. Conversely, low CD80 expression by APCs, along with increased PD-1 and PD-L2 expression in PD-L1-/- mice suggests alternative T cell signaling pathways, leading to a suppressor phenotype. These results suggest that agents (for example antibodies) that can target and neutralize PD-L1/2 may have therapeutic potential for treatment of human stroke.

Original languageEnglish (US)
Article number111
JournalJournal of Neuroinflammation
Volume10
DOIs
StatePublished - Sep 9 2013

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Central Nervous System
Stroke
Inflammation
T-Lymphocytes
Antigen-Presenting Cells
CD80 Antigens
Middle Cerebral Artery Infarction
Monocytes
Ischemia
Ligands
Brain
Microglia
Inbred C57BL Mouse
Knockout Mice
Interleukin-10
Reperfusion
Atrophy
Phenotype
Antibodies

Keywords

  • Co-inhibitory pathway
  • Inflammatory states
  • MCAO
  • Programmed death-1 ligand 1 and 2

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology
  • Neuroscience(all)

Cite this

PD-L1 enhances CNS inflammation and infarct volume following experimental stroke in mice in opposition to PD-1. / Bodhankar, Sheetal; Chen, Yingxin; Vandenbark, Arthur; Murphy, Stephanie J.; Offner, Halina.

In: Journal of Neuroinflammation, Vol. 10, 111, 09.09.2013.

Research output: Contribution to journalArticle

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keywords = "Co-inhibitory pathway, Inflammatory states, MCAO, Programmed death-1 ligand 1 and 2",
author = "Sheetal Bodhankar and Yingxin Chen and Arthur Vandenbark and Murphy, {Stephanie J.} and Halina Offner",
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T1 - PD-L1 enhances CNS inflammation and infarct volume following experimental stroke in mice in opposition to PD-1

AU - Bodhankar, Sheetal

AU - Chen, Yingxin

AU - Vandenbark, Arthur

AU - Murphy, Stephanie J.

AU - Offner, Halina

PY - 2013/9/9

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N2 - Background: Stroke severity is worsened by recruitment of inflammatory immune cells into the brain. This process depends in part on T cell activation, in which the B7 family of co-stimulatory molecules plays a pivotal role. Previous studies demonstrated more severe infarcts in mice lacking programmed death-1 (PD-1), a member of the B7 family, thus implicating PD-1 as a key factor in limiting stroke severity. The purpose of this study was to determine if this protective effect of PD-1 involves either of its ligands, PD-L1 or PD-L2.Methods: Central nervous system (CNS) inflammation and infarct volume were evaluated in male PD-L1 and PD-L2 knockout (-/-) mice undergoing 60 minutes of middle cerebral artery occlusion (MCAO) followed by 96 hours of reperfusion and compared to wild-type (WT) C57BL/6J mice.Results: PD-L1-/- and PD-L2-/- mice had smaller total infarct volumes compared to WT mice. The PD-L1-/- and to a lesser extent PD-L2-/- mice had reduced levels of proinflammatory activated microglia and/or infiltrating monocytes and CD4+ T cells in the ischemic hemispheres. There was a reduction in ischemia-related splenic atrophy accompanied by lower activation status of splenic T cells and monocytes in the absence of PD-L1, suggesting a pathogenic rather than a regulatory role for both PD-1 ligands (PD-Ls). Suppressor T cells (IL-10-producing CD8+CD122+ T cells) trafficked to the brain in PD-L1-/- mice and there was decreased expression of CD80 on splenic antigen-presenting cells (APCs) as compared to the WT and PD-L2-/- mice.Conclusions: Our novel observations are the first to implicate PD-L1 involvement in worsening outcome of experimental stroke. The presence of suppressor T cells in the right MCAO-inflicted hemisphere in mice lacking PD-L1 implicates these cells as possible key contributors for controlling adverse effects of ischemia. Increased expression of CD80 on APCs in WT and PD-L2-/- mice suggests an overriding interaction leading to T cell activation. Conversely, low CD80 expression by APCs, along with increased PD-1 and PD-L2 expression in PD-L1-/- mice suggests alternative T cell signaling pathways, leading to a suppressor phenotype. These results suggest that agents (for example antibodies) that can target and neutralize PD-L1/2 may have therapeutic potential for treatment of human stroke.

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