Abstract

Infiltrating monocyte-derived macrophages (M-MΦ) influence stroke-induced brain injury. Although the inflammatory nature of M-MΦ in acute stroke has been well documented, their role during the resolution phase of stroke is less clear. With emerging evidence for the involvement of scavenger receptors in innate immunity, this study addresses an M-MΦ CD36 role in mediating phagocytosis during the recovery phase of stroke. Stroke increases CD36 and TSP-1/2 mRNA levels in the ipsilateral hemisphere at acute (3-day (d)) and recovery (7d) periods. Quantification of total, intracellular, and cell surface CD36 protein levels showed relatively unchanged expression at 3d post-ischemia. At 7d, there was a significant increase in cell surface CD36 (p < 0.05) with a concurrent reduction of intracellular CD36 (p < 0.05) in the ipsilateral hemisphere. Both cell surface and intracellular CD36 were found in whole brain lysates, whereas cell surface CD36 was predominantly detected in isolated brain mononuclear cells, blood monocytes, and peritoneal macrophages, suggesting that cell surface CD36 expressed in the post-ischemic brain originates from the periphery. The stroke-induced CD36 mRNA level correlated with increased expression of lysosomal acid lipase, an M2 macrophage marker. Functionally, higher CD36 expression in M-MΦ is correlated with higher phagocytic indices in post-ischemic brain immune cells. Moreover, pharmacological inhibition of CD36 attenuated phagocytosis in peritoneal macrophages and brain M-MΦ These findings demonstrate that cell surface CD36 on M-MΦ mediates phagocytosis during the recovery phase in post-stroke brains and suggests that CD36 plays a reparative role during the resolution of inflammation in ischemic stroke.

Highlights

  • Tional studies addressing stroke-induced inflammation and immunity have largely focused on the acute phase of stroke

  • With a limited current understanding of the events that underlie the transition from the post-stroke inflammation phase to the resolution phase, this study addresses the involvement of CD36 in the resolution of post-stroke inflammation

  • As an innate immune receptor expressed in peripheral monocytes/macrophages, key findings from this study include the presence of two distinct forms of CD36 protein, intracellular and cell surface CD36, in the post-ischemic brain and a specific increase of cell surface CD36 in M-M⌽ during the 7d resolution phase

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Summary

The abbreviations used are

M-M⌽, monocyte-derived macrophage(s); TSP, thrombospondin; MCAO, middle cerebral artery occlusion; d, day(s); LAL, lysosomal acid lipase; SAB, salvianolic acid B; CBF, cerebral blood flow; PE, phycoerythrin; ANOVA, analysis of variance; Contra, contralateral; Ipsi, ipsilateral; iNOS, inducible nitric oxide synthase; Cy7, cyanine 7; APC, allophycocyanin; ARRIVE, Animal Research: Reporting of in Vivo Experiments. CD36-mediated Phagocytosis in Ischemic Stroke have shown that CD36 contributes to acute ischemic brain injury [18, 19], apparently mediated by CD36 expressed in endothelial cells [20]. Hemorrhagic and neonatal stroke studies showed a beneficial side of CD36 through enhancing phagocytic function [21,22,23]. These reports of detrimental and beneficial outcomes indicate a context-dependent role for CD36 involving inflammation and resolution. We report that cell surface CD36 protein expression in M-M⌽ increases at the resolution phase of stroke and contributes to phagocytosis in the ischemic brain, demonstrating a post-stroke stage-specific role of CD36 in ischemic stroke

Results
Discussion
Experimental Procedures
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