Pathologic Role of Bacterial Cyclic Dinucleotides in Sepsis

摘要 败血症是一种威胁生命的器官功能障碍，由宿主对感染的反应失调引起，是一种主要的 治疗选择有限的公共卫生问题。尽管对炎症信号进行了广泛的研究 在转导方面，脓毒症的病理生理学仍知之甚少。我们最近提供了证据来支持 间变性淋巴瘤激酶(ALK)，一种与肿瘤相关的受体酪氨酸激酶，在肿瘤中的新作用 致死性脓毒症时细菌环二核苷酸(CDN)诱导的天然免疫调节。基因 ALK表达中断降低干扰素基因刺激物(STING)介导的宿主免疫 单核细胞和巨噬细胞对CDN的反应。从机制上讲，碱性磷酸酶直接与表皮相互作用 生长因子受体(EGFR)激活AKT磷酸化和激活干扰素调节因子3(IRF3) 和核因子κB(NF-κB)信号通路，实现依赖刺痛的严格炎症反应。 值得注意的是，对ALK-STING通路的药理或遗传抑制可提供对致死性脓毒症的保护 在更年轻的小鼠身上。这些令人兴奋的发现提出了几个关于以前未确定的 细菌CDN信号在脓毒症中的病理作用。我们的中心假设是ALK-STING途径是一种 脓毒症致死性炎症和凝血的前瞻性新的关键治疗靶点。为了测试这一点 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：明确在宿主对CDNS的反应中，ALK介导的STING激活的分子机制。目标2. 明确在宿主对CDNS的反应中，ALK介导的刺痛释放的分子机制。目标3.评估 靶向ALK-STING通路对老年小鼠脓毒症的保护作用完成 这些令人兴奋的研究不仅将确定脓毒症治疗的潜在策略，而且还将提供新的 细菌CDN在致死性炎症中的病理作用。

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.