Islam Rezwanul, Choudhary Hadi Hasan, Zhang Feng, Mehta Hritik, Yoshida Jun, Thomas Ajith, Hanafy Khalid
Cooper Medical School of Rowan University Camden NJ USA.
Department of Neurology Cooper University Health Care Camden NJ USA.
J Am Heart Assoc. 2025 May 6;14(9):e039409. doi: 10.1161/JAHA.124.039409. Epub 2025 Apr 25.
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.
Lyn激酶是酪氨酸激酶Src家族的成员，主要因其在调节免疫细胞信号传导中的作用而闻名。它可以磷酸化并调节参与免疫反应的各种蛋白质的活性，包括Toll样受体4（TLR4）。TLR4介导的炎症途径已得到广泛研究；然而，TLR4与Lyn在动脉瘤性蛛网膜下腔出血（SAH）后神经炎症中的性别特异性相互作用尚未得到研究。SAH是由动脉瘤破裂引起的，其后果往往导致神经炎症和认知障碍。在我们的研究中，我们研究了Lyn激酶在调节TLR4信号传导中的性别特异性参与情况，以了解SAH后TLR4介导的炎症反应。
本研究使用了两性细胞特异性Lyn基因敲除小鼠。在SAH手术后第7天，通过多色流式细胞术、免疫组织化学和蛋白质印迹法对野生型和条件性基因敲除小鼠的大脑进行分析。对冷冻的小鼠脑组织进行了无偏倚的空间转录组分析。还使用了三维脑卒模型和SAH患者的脑脊液样本进行本研究。
我们从流式细胞术、免疫组织化学、蛋白质印迹、认知功能测试和空间转录组数据中获得的总体动物和患者数据显示，Lyn激酶是炎症细胞因子产生、红细胞吞噬、神经元凋亡和认知功能的性别特异性调节因子，也是TLR4信号通路的负调节因子。
我们的结果突出了出血性中风后Lyn激酶活性在TLR4信号传导中的性别特异性调节作用，并表明成功治疗神经炎症可能需要针对性别的治疗。
