Pathologic Role of Bacterial Cyclic Dinucleotides in Sepsis

摘要 脓毒症是一种由宿主对感染的反应失调引起的危及生命的器官功能障碍， 公共卫生问题，治疗选择有限。尽管对炎症信号的广泛研究 尽管脓毒症的病理生理学与细胞转导有关，但仍知之甚少。我们最近提供的证据 间变性淋巴瘤激酶（ALK）是一种肿瘤相关受体酪氨酸激酶， 细菌环二核苷酸（CDN）诱导的先天性免疫在致死性脓毒症的调节。遗传 ALK表达的破坏减少了干扰素基因（STING）介导的宿主免疫刺激物 在单核细胞和巨噬细胞中对CDN的反应。在机制上，ALK直接与表皮相互作用 生长因子受体（EGFR），触发AKT磷酸化并激活干扰素调节因子3（IRF 3） 和核因子κB（NF-κB）信号通路，从而实现STING依赖性的严格炎症反应。 值得注意的是，ALK-STING途径的药理学或遗传学抑制可提供针对致死性脓毒症的保护 年轻的老鼠。这些令人兴奋的发现提出了几个重要的问题， 细菌CDN信号传导在脓毒症中的病理作用。我们的中心假设是ALK-STING通路是一个 脓毒症致死性炎症和凝血的潜在新的和关键的治疗靶点。为了验证这一 假设，我们将利用互补的分子，细胞和动物模型来追求以下目标。 目的1：确定ALK介导的STING活化在宿主对CDN应答中的分子机制。目标2. 定义宿主对CDN应答中ALK介导的STING释放的分子机制。目标3.评价 靶向ALK-STING通路在老年小鼠中预防脓毒症的功效。完成 这些令人兴奋的研究不仅将确定脓毒症治疗的潜在策略， 关于细菌CDN在致命炎症中的病理作用的观点。

Abstract Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major public health concern with limited therapeutic options. Despite extensive studies on inflammatory signal transduction, the pathophysiology of sepsis is still poorly understood. We recently provided evidence to support a novel role for the anaplastic lymphoma kinase (ALK), a tumor-associated receptor tyrosine kinase, in the regulation of bacterial cyclic dinucleotide (CDN)-induced innate immunity during lethal sepsis. The genetic disruption of ALK expression diminishes the stimulator of interferon genes (STING)-mediated host immune response to CDNs in monocytes and macrophages. Mechanistically, ALK directly interacts with the epidermal growth factor receptor (EGFR) to trigger AKT phosphorylation and activate interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling pathways, enabling STING-dependent rigorous inflammatory responses. Notably, pharmacological or genetic inhibition of the ALK-STING pathway confers protection against lethal sepsis in younger mice. These exciting findings raise several important questions regarding the previously unidentified pathologic role of bacterial CDN signaling in sepsis. Our central hypothesis is that the ALK-STING pathway is a prospective new and key therapeutic target for lethal inflammation and coagulation in sepsis. To test this hypothesis, we will exploit complementary molecular, cellular, and animal models to pursue the following aims. Aim 1: Define the molecular mechanism of ALK-mediated STING activation in host responses to CDNs. Aim 2. Define the molecular mechanism of ALK-mediated STING release in host responses to CDNs. Aim 3. Evaluate the efficacy of targeting the ALK-STING pathway in protecting against sepsis in aged mice. The completion of these exciting studies will not only identify a potential strategy for sepsis therapy, but also provide new perspectives on the pathologic role of bacterial CDNs in lethal inflammation.