# Immune-mediated mechanisms underlying conditioning-induced stroke recovery

> **NIH NIH R01** · WINIFRED MASTERSON BURKE MED RES INST · 2021 · $525,933

## Abstract

Stroke is the leading cause of physical disability worldwide and is a global socioeconomic burden to human
health. Brain injury from stroke is typically considered an exclusively CNS event, but injury progression
and repair processes are profoundly influenced by peripheral immunity. Ischemic Limb Conditioning [LC]
has been shown to trigger an endogenous protective phenomenon that provides tolerance and protection
against stroke and cardiovascular diseases. Because LC is applied remotely from the injured brain, its
beneficial effects may be mediated by peripheral immune cells, but there have been only a limited number
of studies into interactions between the nervous and peripheral immune systems after stroke. To address
the gap in our knowledge, this proposal will investigate if and how LC alters the peripheral immune system
and whether LC improves acute outcome and chronic recovery in stroke. Our preliminary findings in C57
mice show that LC shifts circulating monocytes to a pro-inflammatory [MoPro] state. These findings also
show that this MoPro shift does not occur in mice deficient for CD36, an inflammatory receptor highly
expressed in monocytes. Moreover, post-stroke application of LC reduces infarct size, brain swelling, and
profoundly enhances motor/gait function in chronic stroke. The improved function is associated with less
neuronal loss in the substantia nigra, an area where secondary transneuronal degeneration has been
observed in stroke involving the striatum. Despite the established detrimental role of MoPro in promoting
acute tissue damage, our observations indicate that MoPro has a beneficial role in LC-induced functional
recovery. Thus, we hypothesize that the LC-induced MoPro shift enhances resolution of inflammation at the
primary injury site in a CD36-dependent manner, and promotes stroke recovery by counteracting
secondary degeneration. Aim 1 will use loss- and gain-of-function studies to establish the critical role of
MoPro for LC-induced benefits in stroke outcome. In Aim 2, we will identify and validate CD36 as an
upstream mediator of the LC-induced monocyte shift. To address in vivo mechanism of LC-enhanced
functional outcome, Aim 3 will investigate whether LC counteracts secondary degeneration in the
substantia nigra and thalamus after stroke. In Aim 4, we will establish the frequency and time of secondary
degeneration in the substantia nigra and thalamus from databases of stroke patients with basal ganglia
injury. The successful completion of this project is expected to have an important and positive impact
because it will provide an evidence-based framework for the subsequent development of translational
strategies to use LC in order to improve functional recovery in chronic stroke.

## Key facts

- **NIH application ID:** 10120747
- **Project number:** 5R01NS111568-03
- **Recipient organization:** WINIFRED MASTERSON BURKE MED RES INST
- **Principal Investigator:** Sunghee Cho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $525,933
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120747

## Citation

> US National Institutes of Health, RePORTER application 10120747, Immune-mediated mechanisms underlying conditioning-induced stroke recovery (5R01NS111568-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10120747. Licensed CC0.

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