CD36 in the periphery and brain synergizes in stroke injury in hyperlipidemia

Abstract

Objective Hyperlipidemia exacerbates ischemic stroke outcome and increased CD36 expression in the post-ischemic brain as well as in peripheral monocytes/macrophages. By exchanging bone marrow-derived cells between CD36-expressing and –deficient mice, this study investigates the contribution of peripheral CD36 vs brain CD36 to stroke pathology in hyperlipidemia. Methods Following bone marrow transplantation, mice were fed a high fat diet for 11 weeks, and then subjected to ischemic stroke. Stroke outcome, expression of brain CD36, MCP-1, CCR2, and plasma MCP-1 levels were determined at 3 days post-ischemia. CD36 and CCR2 expression were also determined in splenocytes incubated with serum obtained from CD36-expressing or CD36-deficient mice. Results Infiltrating immune cells from the periphery are the major source of CD36 in the post-ischemic brain and contribute to stroke-induced brain injury. This CD36 effect was dependent on the modulation of MCP-1 and CCR2 expression in peripheral immune cells as well as CD36-expressing cells in the host brain. Interpretation This study demonstrates that CD36 expressed in the periphery and brain synergize in ischemic brain injury through regulation of the MCP-1/CCR2 chemokine axis in hyperlipidemic conditions.

Microglia and Monocyte-Derived Macrophages in Stroke

“…A subsequent study revealed the involvement of CD36 expression in peripheral mononuclear phagocytes and CNS for hyperlipidemia-induced exacerbation of infarct volume and brain edema. By exchanging bone marrow cells between CD36-expressing and CD36-deficient mice, the study demonstrated that CD36 regulates MCP-1/CCR2 expression in the host and macrophages, suggesting the involvement of CD36 in monocyte trafficking in hyperlipidemic conditions [101]. While the observed effect is likely mediated through the proinflammatory CCR2 + subset considering the major expansion of the CCR2 + (Ly-6C hi ) subset in hyperlipidemic conditions, the relative contribution of the CCR2 -(Ly-6C low ) subset and its function remain to be explored.…”

“…In contrast, the absence of CCR2 or MCP-1 led to reduced infarct size [96,100]. Relevant to the MCP-1/CCR2 axis in monocyte trafficking, a study demonstrated involvement of the scavenger receptor CD36 in exacerbating stroke-induced injury in hyperlipidemic mice [101]. The exacerbation was linked to the role of CD36 in regulating MCP-1 expression in a host-specific manner and CCR2 expression on immune cells, showing the influence of peripheral immunity on the CNS via the MCP-1/CCR2 axis.…”

“…These anti-inflammatory Ly-6C lo (CCR2 -/ CX3CR1 + ) monocytes are recruited to normal tissues and develop into resident M2 macrophages that function in host defense and repair after injury [102]. Compared with the proinflammatory MCP-1/CCR2 axis, there was less involvement of the anti-inflammatory CX3CL1 (fractalkine)/CX3CR1 axis in the acute phase of stroke [101], which may be related to less recruitment of Ly-6C lo subsets in the ischemic brain at this time point [25].…”

“…CD36 is highly expressed in microglia, monocytes/macrophages, microvascular endothelial cells, platelets, and epithelial cells and it regulates inflammation, innate immunity, angiogenesis, and lipid metabolism through interactions with lipid and nonlipid-based ligands [151]. 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].…”

“…These conditions are often associated with the exacerbation of ischemic outcomes and are predictive of worse recovery [186]. The inclusion of hyperlipidemia and diabetes in animal models of stroke has demonstrated that these conditions modulate postischemic inflammatory responses and lesion development [101,152,187,188]. In addition, increased inflammatory factors such as cytokines, chemokines, and adhesion molecules in peripheral monocytes/macrophages in these conditions suggest that peripheral immune status modulates CNS injury.…”