Award Title: Intermittent fasting mediated metabolic reprogramming reshapes the T cell immunity and preserves white matter integrity after stroke
Funder: The Academy of Medical Sciences

Abstract: Ischemic stroke is the world's leading cause of disability and is particularly prevalent in the huge population of hypertensive patients. Hypertension also has an unfavourable effect on neurological outcome of stroke patients, thus posing an enormous burden to the patients' families and the society both in China and the UK. So far, there are only few effective ways to improve the neurological recovery after stroke, and those are restricted to selected patients and ultra-short time windows, exluding most patients from treatment. The impact of T cells on the ischemic brain injury lasts long into the late phase of stroke. We found that intermittent fasting, as a caloric restricted dietary management strategy, had profound impact on the fate of T cells that could be favourable for stroke patients. Therefore, we propose that by adjusting the hypertensive patients' diet, we may change the stroke patients' T cell fates into a less damaging but more healing type thus improving neurological outcomes after stroke by altering gene transcripts from the T cellsâ€™metabolic molecules. Dietary intake is the everyday essential for all patients and intermittent fasting is a cheap yet effective dietary management that is attracting increasing attention in treating various diseases. The findings of this project can give insights into the protection mechanism of intermittent fasting for ischemic stroke and may potentially benefit the huge population around the world with stroke or at high risks of stroke, which in turn would reduce the global economic and social burden of chronic disability attributable to stroke.

Lay Abstract: Ischemic stroke leads to severe and long lasting neurological deficts. White matter injury attributable to hypertension-related cerebral small vessel disease and ischemic stroke itself is gaining increased attention due to its additional devastating effects on the brain. Demyelination is a critical feature of white matter injury and it can elicit profound activation of antigen-specific adaptive T cells. Importantly, glycolysis and fatty acid synthesis are two critical metabolic checkpoints in determining the fate of T cell differentiation, with pro-inflammatory Th17 cells highly relying on the energy supply for proliferation. In contrast, anti-inflammatory regulatory T cells (Tregs) are less dependent on glycolysis and fatty acid synthesis. Therefore, metabolic modulation of T cells is emerging as a promising strategy for the treatment of neuroinflammatory disorders. We previously found that cerebral ischemic stroke induces significantly increased glycolysis and fatty acid synthesis in the peripheral T cells, which in turn polarizes T cells into Th17 cells instead of Tregs, both of which play important but distinct roles in the cerebral ischemic brain injury. In a preliminary study, we found that intermittent fasting, a potent calorie-restrictive diet, can significantly inhibit the expression of Foxk1, a forkhead transcription factor regulating glycolysis in CD4+ T cells, thus putting forward the hypothesis: intermittent fasting can reshape the differentiation of CD4+ T cells into more regulatory T cells but less Th17 cells after stroke. Foxk1 may serve as a critical regulator of the metabolic reprogramming of T cells after intermittent fasting which contributes to the attenuation of T cell-mediated white matter injury after ischemic stroke with or without hypertension. This collaborative project between China and the UK soughts to address the above hypothesis by 1) establishing a more clinically relevant hypertensive stroke mice model and generating the T cell-specific Foxk1 conditional knockout mice; 2) performing RNA sequencing, targeted lipodomics and seahorse glycolytic stress tests in flow cytometry sorted CD4+ T cells from intermittent fasting-treated hypertensive mice. This project may lead to a translation-friendly complementary stroke therapy in the context of hypertension and white matter injury that can improve long term neurological functions. Meanwhile, digging into the underlying mechanisms of intermittent fasting-mediated immunomodulation for secondary brain protection may also advance the current understanding of the metabolic reprogramming of post-stroke T cell responses and pave the way for the discovery of novel metabolic immune modulatory targets for stroke.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CARDIOVASCULAR;STROKE