Ischemic Conditioning Promotes Transneuronal Survival and Stroke Recovery via CD36-Mediated Efferocytosis.

Document Type

Article

Publication Date

2-28-2025

Publication Title

Circulation research

Keywords

JCA, Animals, CD36 Antigens, Recovery of Function, Phagocytosis, Mice, Mice, Inbred C57BL, Male, Ischemic Preconditioning, Macrophages, Mice, Knockout, Monocytes, Ischemic Stroke, Neurons, Cell Survival, Efferocytosis

JAX Source

Circ Res. 2025;136(5):e34-e51.

Volume

136

Issue

5

First Page

34

Last Page

34

ISSN

1524-4571

PMID

39886760

DOI

https://doi.org/10.1161/CIRCRESAHA.124.325428

Abstract

BACKGROUND: Remote ischemic conditioning (RIC) has been implicated in cross-organ protection in cerebrovascular disease, including stroke. However, the lack of a consensus protocol and controversy over the clinical therapeutic outcomes of RIC suggest an inadequate mechanistic understanding of RIC. The current study identifies RIC-induced molecular and cellular events in the blood, which enhance long-term functional recovery in experimental cerebral ischemia.

METHODS: Naive mice or mice subjected to transient ischemic stroke were randomly selected to receive sham conditioning or RIC in the hindlimb at 2 hours post-stroke. At 3 days post-stroke, monocyte composition in the blood was analyzed, and brain tissue was examined for monocyte-derived macrophage (Mφ), levels of efferocytosis, and CD36 expression. Mouse with a specific deletion of CD36 in monocytes/Mφs was used to establish the role of CD36 in RIC-mediated modulation of efferocytosis, transneuronal degeneration, and recovery following stroke.

RESULTS: RIC applied 2 hours after stroke increased the entry of monocytes into the injured brain. In the postischemic brain, Mφ had increased levels of CD36 expression and efferocytosis. These changes in brain Mφ were derived from RIC-induced changes in circulating monocytes. In the blood, RIC increased CD36 expression in circulating monocytes and shifted monocytes to a proinflammatory Lymphocyte antigen 6 complex (LY6C)

CONCLUSIONS: RIC induces a shift in monocytes to a proinflammatory state with elevated CD36 levels, and this is associated with CD36-dependent efferocytosis in Mφs that rescues delayed transneuronal degeneration in the postischemic brain and promotes stroke recovery. Together, these findings provide novel insight into our mechanistic understanding of how RIC improves poststroke recovery.

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