Introduction CD36 is a pleiotropic receptor involved in several pathophysiological conditions, including cerebral ischemia, neurovascular dysfunction and atherosclerosis. 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. Methods Mice received sham T10 laminectomies or 50 kdyn contusions using the IH impactor and were functionally assessed using the Basso Mouse Scale (BMS) one week prior to surgery and weekly after SCI. Treadcan analysis of mice placed on a motor-driven translucent treadmill was performed as described (Beare et al., 2009). Mice were anesthetized and the intravital marker FITC-LEA was delivered systemically prior to transcardial perfusion. Spinal cords were dissected, snap frozen, longitudinally sectioned at 20 (mu)m, and mounted on slides for immunohistochemical staining. Primary murine cortex endothelial cell isolation was adapted from protocols as described (Hoying et al., 1996). All images were captured with a Nikon TE 300 inverted microscope equipped with a Spot CCD camera using identical exposure settings. All image quantitation was performed using Elements software using identical threshhold parameters and settings. Results Following contusive injury, CD36-/- mice demonstrated improved hindlimb functional recovery, and the lesion area of contused CD36-/- mice was significantly smaller 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 4HNEinduced phospho-ATF4 and CHOP expression. A reduction in phospho- eIF2a and subsequent increase in KDEL-positive, ER-localized proteins suggest that 4HNE-CD36 signaling facilitates the detection of misfolded proteins upstream of eIF2a phosphorylation, ultimately leading to CHOP-induced apoptosis. Conclusions 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 stressinduced cell death within endothelial and macrophage cells following injury.
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