Genetic deletion of CD36 enhances injury after acute neonatal stroke

Abstract

OBJECTIVES The scavenger receptor CD36 is injurious in acute experimental focal stroke and neurodegenerative diseases in the adult. We investigated the effects of genetic deletion of CD36 (CD36ko) on acute injury, and oxidative and inflammatory signaling after neonatal stroke. METHODS P9 CD36ko and wild type (WT) mice were subjected to a transient middle cerebral artery occlusion (MCAO). Injury, phagocytosis of dying cells, and CD36 inflammatory signaling were determined. RESULTS While the volume of “tissue at risk” by diffusion-weighted MRI during MCAO was similar in neonatal CD36ko and WT mice, by 24 hrs after reperfusion, injury was more severe in CD36ko and was associated with increased caspase-3 cleavage and reduced engulfment of neurons expressing cleaved caspase-3 by activated microglia. No significant superoxide generation was observed in activated microglia in injured WT whereas increased superoxide production in vessels and NFκB activation induced by MCAO were unaffected by lack of CD36. While Lyn expression was higher in injured CD36ko, cell-type specific patterns of Lyn expression were altered; Lyn was expressed in endothelial cells and microglia in WT but predominantly in dying neurons in CD36ko. Interpretation Lack of CD36 results in poorer short-term outcome from neonatal focal stroke due to lack of attenuation of NFκB-mediated inflammation and diminished removal of apoptotic neuronal debris. While inhibition of CD36 does not seem to be a good therapeutic target for protection after acute neonatal stroke, like it is after adult stroke, seeking better understanding of CD36 signaling in particular cell populations may reveal important therapeutic targets for neonatal stroke.

Microglia and Monocyte-Derived Macrophages in Stroke

“…Several studies demonstrated that CD36 expression is upregulated in the ischemic brain [152], and that CD36 is involved in stroke-induced inflammation and injury [101,[152][153][154]. Despite the detrimental effects of CD36 in an acute ischemic setting, CD36-dependent phagocytosis was associated with functional benefit in neonatal stroke [155]. Additionally, the clearing of red blood cells after hemorrhagic stroke was associated with increased CD36 expression and improved functional recovery [156].…”

Mechanisms of Perinatal Arterial Ischemic Stroke

“…Depletion of these cells or genetic deletion of the scavenger receptor CD36, a receptor that participates in the recognition and engulfment of apoptotic cells by microglia and macrophages, worsens injury and leads to accumulation of apoptotic neurons that die by caspase-3-dependent mechanisms. 13,90 The distinct patterns of superoxide Brain immaturity affects stroke mechanisms D Fernández-Ló pez et al accumulation in microglia/macrophages after acute adult 125 and neonatal 13,90 stroke may be central to the age-related differences in stroke mechanisms.…”

Cell Surface CD36 Protein in Monocyte/Macrophage Contributes to Phagocytosis during the Resolution Phase of Ischemic Stroke in Mice

“…Genetic deletion and pharmacological intervention studies * This work was supported by National Institutes of Health Grants have shown that CD36 contributes to acute ischemic brain injury (18,19), apparently mediated by CD36 expressed in endothelial cells (20). On the other hand, hemorrhagic and neonatal stroke studies showed a beneficial side of CD36 through enhancing phagocytic function (21)(22)(23). Therefore, these reports of detrimental and beneficial outcomes indicate a context-dependent role for CD36 involving inflammation and resolution.…”