title: Endothelial CD36 Contributes to Postischemic Brain Injury by Promoting Neutrophil Activation via CSF3.
abstract: The scavenger receptor CD36 is a critical factor initiating ischemic brain injury, but the cell type(s) expressing CD36 and responsible for its harmful effects remain unknown. Using bone marrow (BM) chimeras subjected to transient middle cerebral artery occlusion, we found that CD36(-/-) mice transplanted with wild-type (WT) BM (WT→CD36(-/-)) have smaller infarcts (-67%), comparable with those of mice lacking CD36 both in brain and hematogenous cells (CD36(-/-) →CD36(-/-); - 72%). Conversely, WT mice receiving CD36(-/-) BM (CD36(-/-) →WT) have infarcts similar to WT→WT mice, suggesting that CD36 in the host brain (i.e., in microglia and endothelial cells), and not in hematogenous cells is involved in the damage. As anticipated, postischemic neutrophil infiltration in CD36(-/-) →CD36(-/-) mice was attenuated. Surprisingly, however, in WT→CD36(-/-) mice, in which infarcts were small, neutrophil infiltration was large and similar to that of CD36(-/-) →WT mice, in which infarcts were not reduced. Postischemic neutrophil free radical production was attenuated in WT→CD36(-/-) mice compared with CD36(-/-) →WT mice, whereas expression of the neutrophil activator colony-stimulating factor 3 (CSF3) was suppressed in CD36(-/-) cerebral endothelial cells, but not microglia. In CD36(-/-) cerebral endothelial cultures exposed to extracts from stroke brains, the upregulation of CSF3, but not neutrophil attractant chemokines, was suppressed. Intracerebroventricular administration of CSF3, 24 h after stroke, reconstituted neutrophil radical production and increased infarct volume in WT→CD36(-/-) mice. The findings identify endothelial cells as a key player in the deleterious effects of CD36 in stroke, and unveil a novel role of endothelial CD36 in enabling neutrophil neurotoxicity through CSF3.
  
  
  CONCLUSIONS
  Ischemic stroke is a leading cause of death and disability worldwide with limited therapeutic options. The inflammatory response initiated by cerebral ischemia-reperfusion contributes to ischemic brain injury and is a potential therapeutic target. Here we report that CD36, an innate immunity receptor involved in the initiation of postischemic inflammation, is a previously unrecognized regulator of neutrophil cytotoxicity. The effect is mediated by endothelial CD36 via upregulation of the neutrophil activator CSF3 in cerebral endothelial cells. Therefore, approaches to modulate cerebral endothelial CD36 signaling or to neutralize CSF3 may provide novel therapeutic opportunities to ameliorate postischemic inflammatory injury.
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Lidia
authors.initials: L
authors.lastname: Garcia-Bonilla
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Racchumi
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Michelle
authors.initials: M
authors.lastname: Murphy
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065 coi2001@med.cornell.edu.
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D018955:CD36 Antigens / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000502:physiology*; D009924:Organ Culture Techniques; D016184:Receptors, Colony-Stimulating Factor / Q000096:biosynthesis*
chemical_list: D018955:CD36 Antigens; C517047:CSF3R protein, human; D016184:Receptors, Colony-Stimulating Factor
keywords: flow cytometry; free radicals; postischemic inflammation; scavenger receptor; stroke