CD84 Links T Cell and Platelet Activity in Cerebral Thrombo-Inflammation in Acute Stroke

Circ Res. 2020 Sep 25;127(8):1023-1035. doi: 10.1161/CIRCRESAHA.120.316655. Epub 2020 Jul 30.

Abstract

Rationale: Ischemic stroke is a leading cause of morbidity and mortality worldwide. Recanalization of the occluded vessel is essential but not sufficient to guarantee brain salvage. Experimental and clinical data suggest that infarcts often develop further due to a thromboinflammatory process critically involving platelets and T cells, but the underlying mechanisms are unknown.

Objective: We aimed to determine the role of CD (cluster of differentiation)-84 in acute ischemic stroke after recanalization and to dissect the underlying molecular thromboinflammatory mechanisms.

Methods and results: Here, we show that mice lacking CD84-a homophilic immunoreceptor of the SLAM (signaling lymphocyte activation molecule) family-on either platelets or T cells displayed reduced cerebral CD4+ T-cell infiltration and thrombotic activity following experimental stroke resulting in reduced neurological damage. In vitro, platelet-derived soluble CD84 enhanced motility of wild-type but not of Cd84-/- CD4+ T cells suggesting homophilic CD84 interactions to drive this process. Clinically, human arterial blood directly sampled from the ischemic cerebral circulation indicated local shedding of platelet CD84. Moreover, high platelet CD84 expression levels were associated with poor outcome in patients with stroke.

Conclusions: These results establish CD84 as a critical pathogenic effector and thus a potential pharmacological target in ischemic stroke.

Keywords: T lymphocytes; blood platelets; brain ischemia; infarction; stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Blood Coagulation
  • Blood Platelets / metabolism*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Chemotaxis, Leukocyte
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / immunology
  • Infarction, Middle Cerebral Artery / metabolism*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Prospective Studies
  • Signal Transduction
  • Signaling Lymphocytic Activation Molecule Family / genetics
  • Signaling Lymphocytic Activation Molecule Family / metabolism*
  • Thrombotic Stroke / genetics
  • Thrombotic Stroke / immunology
  • Thrombotic Stroke / metabolism*

Substances

  • CD84 protein, human
  • Cd84 protein, mouse
  • Cytokines
  • Homeodomain Proteins
  • Signaling Lymphocytic Activation Molecule Family
  • RAG-1 protein