Thursday, November 21, 2024
11/21/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
