# Modulation of the TLR4-Lyn interaction in SAH

> **NIH NIH R01** · FLORIDA ATLANTIC UNIVERSITY · 2021 · $443,892

## Abstract

Hemorrhagic stroke affects 160,000 Americans per year and over half of these patients will die by the end of
the year. Treatment for both forms of hemorrhagic stroke, intraparenchymal hemorrhage and aneurysmal
subarachnoid hemorrhage, have been at a virtual standstill for the last 40 years, and not due to lack of effort.
Perhaps the reason for the lack of progress is an inability to effectively address the cerebral inflammation
secondary to the extravasated red blood cell (RBC) burden. In animal models of hemorrhagic stroke, microglia
(MG), the tissue resident macrophages of the brain, have been shown to play a critical role in RBC-induced
cerebral inflammation. The MG receptor that is responsible for initiating RBC-induced cerebral inflammation is
Toll Like Receptor 4 (TLR4). In mouse models of hemorrhagic stroke, MG TLR4 responds to the breakdown
products of RBCs to initiate cerebral inflammation. While inhibiting MG TLR4 would seem feasible to prevent
cerebral inflammation in hemorrhagic stroke, this strategy carries a significant risk of immunosuppression.
Modulation of non-canonical TLR4 pathways that are downstream of TLR4 may offer some respite against
MG-mediated cerebral inflammation.
Lyn kinase (Lyn) is a Src-family tyrosine kinase expressed by B, myeloid, and dendritic cells. Lyn is unique in
the SFK family in that it has both stimulatory and feedback-inhibitory pathways in B cell receptor signaling that
can lead to ligand tolerance. Evidence for Lyn kinase regulation of TLR4 signaling in response to bacterial
PAMPs is scant, contradictory, and cell type dependent. Understanding Lyn regulation of TLR4 signaling in
response to an RBC stimulus in MG is novel, and could allow for the modulation of cerebral inflammation in
hemorrhagic stroke.
Our lab has found that MG TLR4-Lyn signaling is important for RBC-induced inflammation and RBC
phagocytosis. Our preliminary data indicates that modulation of this pathway does indeed decrease neuronal
apoptosis, in vitro. We hypothesize that modulation of this pathway in MG can improve outcome after SAH and
possibly other forms of hemorrhagic stroke.

## Key facts

- **NIH application ID:** 10274359
- **Project number:** 7R01NS109174-03
- **Recipient organization:** FLORIDA ATLANTIC UNIVERSITY
- **Principal Investigator:** Khalid A. Hanafy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $443,892
- **Award type:** 7
- **Project period:** 2020-10-02 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274359

## Citation

> US National Institutes of Health, RePORTER application 10274359, Modulation of the TLR4-Lyn interaction in SAH (7R01NS109174-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10274359. Licensed CC0.

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