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 ?B (NF-?B) 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.
Despite recent advances in antibiotic therapy and intensive care, sepsis and septic shock remain the leading causes of death in intensive care units worldwide, including the United States. We postulate that dysfunction of the ALK-mediated STING pathway is an emerging hallmark of sepsis that can regulate the lethal inflammatory and coagulation response. Our proposal will uncover a novel pathologic role of bacterial cyclic dinucleotides in sepsis and shed light on the development of cancer drugs for sepsis.
| Wang, Ding; Xie, Nan; Gao, Wanli et al. (2018) The ferroptosis inducer erastin promotes proliferation and differentiation in human peripheral blood mononuclear cells. Biochem Biophys Res Commun 503:1689-1695 |
