# Circadian Control of Brain-peripheral Immune Response After Stroke

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $459,035

## Abstract

Circadian control of brain-peripheral immune response after stroke
Aging and circadian rhythm are strong modulators of the immune system, and the immune
response is a major contributor to stroke pathophysiology. But how aging and circadian rhythm
interacts to influence immune response after stroke remains poorly understood. In this project,
we will focus on the brain-to-cervical lymph node signaling pathway (Esposito et al, Nat Commun
2019). Because lymphatic drainage is regulated by circadian rhythm, and circadian rhythm is
altered in aging, we hypothesize that this pathway may provide a novel integrating mechanism
that connects these 3 major factors in stroke pathophysiology: immune response, circadian
phase, and aging.
Pilot data (some published in Esposito et al, Nat Commun 2019 and Nature 2020) suggest that
(i) circadian phase significantly influences the progression of injury after cerebral ischemia; (ii)
Bmal1 expression in brain and HO1 in astrocytes are higher after active phase vs inactive phase
strokes; (iii) higher brain HO1 draining into CLN in active phase stroke may decrease oxidative
stress 4-Hydroxynonenal (4HNE) in CLN lymphatic endothelium; (iv) higher brain HO1 draining
into CLN in active phase stroke may reduce cytotoxic CD8+ T cells (TLR4+) in spleen; (v) CD8+
T cell infiltration and brain endothelial Cxcl10 and Hmgb1 may be lower in active phase stroke;
(vi) CSF drainage from brain to CLN is affected by both circadian phase and aging; (vii) aging
alters HO1 brain-to-CLN drainage in active phase stroke.
We will test this overall hypothesis: Astrocytic HO1 in active phase stroke (ZT13) amplifies
endogenous anti-oxidative stress response in CLN, reduces splenic inflammation, and decreases
brain endothelial inflammation, whereas aging alters circadian genes and HO1 drainage in the
CNS, thus weakening this endogenous protective response in active phase stroke.
In Aim 1, we will dissect circadian effects in brain-cervical lymph node signaling after focal cerebral
ischemia. In Aim 2, we will investigate the effects of circadian rhythm in post-stroke brain
endothelial inflammation. In Aim 3, we will investigate effects of aging in circadian rhythm-
mediated systemic response after focal cerebral ischemia. This project should define new
mechanisms that connect the stroke immune response with circadian biology and aging, thus
provide a new conceptual framework for seeking targets and biomarkers for day-time vs night-
time strokes in aging patients.

## Key facts

- **NIH application ID:** 10893595
- **Project number:** 5R01NS129654-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Elga Esposito
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,035
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893595

## Citation

> US National Institutes of Health, RePORTER application 10893595, Circadian Control of Brain-peripheral Immune Response After Stroke (5R01NS129654-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10893595. Licensed CC0.

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