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Remote limb conditioning (RLC), performed by intermittent interruption of blood flow to a limb, triggers endogenous tolerance mechanisms and improves stroke outcomes. The underlying mechanism for the protective effect involves a shift of circulating monocytes to a Ly6CHigh proinflammatory subset in normal metabolic conditions. The current study investigates the effect of RLC on stroke outcomes in subjects with obesity, a vascular comorbidity. Compared to lean mice, obese stroke mice displayed significantly higher circulating monocytes (monocytosis), increased CD45High monocytes/macrophages infiltration to the injured brain, worse acute outcomes, and delayed recovery. Unlike lean mice, obese mice with RLC at 2 hours post-stroke failed to shift circulating monocytes to pro-inflammatory status and nullified RLC-induced functional benefit. The absence of the monocyte shift was also observed in splenocytes incubated with RLC serum from obese mice, while the shift was observed in the cultures with RLC serum from lean mice. These results showed that the alteration of monocytosis and subsets underlies negating RLC benefits in obese mice and suggest careful considerations of comorbidities at the time of RLC application for stroke therapy. [ABSTRACT FROM AUTHOR]

CD36 expressed in multiple cell types regulates inflammation, vascular function, and innate immunity. Specifically, CD36 in microvascular endothelial cells (ECs) signals to elicit inflammation and causes EC death. This study investigated roles for EC-CD36 on acute stroke pathology in normal and obese conditions. Obesity induced by a high-fat diet (HD) selectively increased CD36 expression in ECs, not in monocytes/macrophages, in the post-ischemic brain. Mice deficient CD36 in ECs (ECCD36−/−) showed reduced injury size and vascular permeability in normal conditions. While control mice fed a HD developed obesity and aggravated stroke injury, ECCD36−/− mice were resistant to develop an obesity phenotype. Subjecting ECCD36−/− mice to stroke resulted in reduced injury size and BBB disruption. Moreover, the mice had reduced MCP-1 and CCR2 gene expression, resulting in reduced monocyte trafficking with improved survival and acute motor function. Reduced MCP-1 and CCR2 expression was still evident in ECCD36−/− mice subjected to severe stroke, suggesting that monocyte trafficking is an infarct-independent metabolic effect associated with specific EC-CD36 deletion. Our findings demonstrate the importance of EC-CD36 in developing vascular comorbidities and suggest that targeting EC-CD36 is a potential preventative strategy to normalize vascular risk factors, leading to improved acute stroke outcomes. [ABSTRACT FROM AUTHOR]

Ameliorating blood–brain barrier disruption and altering scar formation dynamics are potential strategies that may improve post-stroke recovery. CD36 is a class B scavenger receptor that plays a role in innate immunity, inflammation and vascular dysfunction and regulates post-stroke injury, neovascularization, reactive astrogliosis and scar formation. By subjecting WT and CD36KO mice to different MCAo occlusion durations to generate comparable acute lesion sizes, we addressed the role of CD36 in BBB dysfunction, scar formation and recovery. The majority of stroke recovery studies primarily focus on motor function. Here, we employed an extensive behavioral test arsenal to evaluate psychological and cognitive endpoints. While not evident during the acute phase, CD36 deficient mice displayed significantly attenuated BBB leakage and scar formation at three months after stroke compared to wild-type littermates. Assessment of motor (open field, rotarod), anxiety (plus maze, light-dark box), depression (forced swim, sucrose preference) and memory tests (water maze) revealed that CD36 deficiency ameliorated stroke-induced behavioral impairments in activity, hedonic responses and spatial learning and strategy switching. Our findings indicate that CD36 contributes to stroke-induced BBB dysfunction and scar formation in an injury-independent manner, as well as to the chronic motor and neurophysiological deficits in chronic stroke. [ABSTRACT FROM AUTHOR]