Macrophage Lyn Kinase Is a Sex-Specific Regulator of Post-Subarachnoid Hemorrhage Neuroinflammation

Lyn kinase is a member of the Src family of tyrosine kinases, primarily known for its role in regulating immune cell signaling. It can phosphorylate and modulate the activity of various proteins involved in immune responses, including Toll-like receptor 4 (TLR4). TLR4-mediated inflammatory pathways have been extensively studied; however, the sex-specific interaction of TLR4 and Lyn in neuroinflammation after aneurysmal subarachnoid hemorrhage (SAH) has yet to be investigated. SAH occurs due to a ruptured aneurysm, and the consequences often lead to neuroinflammation and cognitive impairments. In our study, we investigated the sex-specific involvement of Lyn kinase in regulating TLR4 signaling to understand the TLR4-mediated inflammatory response after SAH.

Cell-specific Lyn knockout mice of both sexes were used for this study. Wild-type and conditional knockout mouse brains were analyzed by multicolor flow cytometry, immunohistochemistry, and western blotting at postoperative day 7 following SAH surgery. An unbiased spatial transcriptomic analysis was performed with the frozen mouse brain tissues. A 3-dimensional brain stroke model and cerebrospinal fluid samples of patients with SAH were also used for this study.

Our overall animal and patient data from flow cytometry, immunohistochemistry, western blot, cognitive function tests, and spatial transcriptomic data revealed that Lyn kinase is a sex-specific regulator in inflammatory cytokine production, red blood cell phagocytosis, neuronal apoptosis, and cognitive function, as well as a negative regulator of TLR4 signaling pathways.

Our results highlight sex-specific modulation of Lyn kinase activity in TLR4 signaling after hemorrhagic stroke and indicate that successful treatment of neuroinflammation may require sex-specific treatments.