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Exp Neurol. 2014 Jun;256:25-38. doi: 10.1016/j.expneurol.2014.03.016. Epub 2014 Mar 30.

CD36 deletion improves recovery from spinal cord injury.

Author information

1
Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, 511 S. Floyd St., Rm. 616A, Louisville, KY 40202, USA; Department of Neurological Surgery, University of Louisville School of Medicine, 511 S. Floyd St., Rm. 616A, Louisville, KY 40202, USA.
2
Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, 511 S. Floyd St., Rm. 616A, Louisville, KY 40202, USA; Department of Neurological Surgery, University of Louisville School of Medicine, 511 S. Floyd St., Rm. 616A, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 500 S. Preston St., Louisville, KY 40202, USA. Electronic address: haggt1@etsu.edu.
3
Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, 511 S. Floyd St., Rm. 616A, Louisville, KY 40202, USA; Department of Neurological Surgery, University of Louisville School of Medicine, 511 S. Floyd St., Rm. 616A, Louisville, KY 40202, USA; Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, 500 S. Preston St., Rm 916A, Louisville, KY 40202, USA. Electronic address: swhittemore@louisville.edu.

Abstract

CD36 is a pleiotropic receptor involved in several pathophysiological conditions, including cerebral ischemia, neurovascular dysfunction and atherosclerosis, and recent reports implicate its involvement in the endoplasmic reticulum stress response (ERSR). We hypothesized that CD36 signaling contributes to the inflammation and microvascular dysfunction following spinal cord injury. Following contusive injury, CD36(-/-) mice demonstrated improved hindlimb functional recovery and greater white matter sparing than CD36(+/+) mice. CD36(-/-) mice exhibited a reduced macrophage, but not neutrophil, infiltration into the injury epicenter. Fewer infiltrating macrophages were either apoptotic or positive for the ERSR marker, phospho-ATF4. CD36(-/-) mice also exhibited significant improvements in injury heterodomain vascularity and function. These microvessels accumulated less of the oxidized lipid product 4-hydroxy-trans-2-nonenal (4HNE) and exhibited a reduced ERSR, as detected by vascular phospho-ATF4, CHOP and CHAC-1 expression. In cultured primary endothelial cells, deletion of CD36 diminished 4HNE-induced phospho-ATF4 and CHOP expression. A reduction in phospho-eIF2α and subsequent increase in KDEL-positive, ER-localized proteins suggest that 4HNE-CD36 signaling facilitates the detection of misfolded proteins upstream of eIF2α phosphorylation, ultimately leading to CHOP-induced apoptosis. We conclude that CD36 deletion modestly, but significantly, improves functional recovery from spinal cord injury by enhancing vascular function and reducing macrophage infiltration. These phenotypes may, in part, stem from reduced ER stress-induced cell death within endothelial and macrophage cells following injury.

KEYWORDS:

CD36; Endoplasmic reticulum stress response; Inflammation; Macrophage; Microvasculature; Spinal cord injury

PMID:
24690303
PMCID:
PMC4086463
DOI:
10.1016/j.expneurol.2014.03.016
[Indexed for MEDLINE]
Free PMC Article

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