Molecular Regulation of Systemic Inflammation

全身炎症的分子调节

• 批准号: 9888298
• 负责人: Andrea Dorfleutner
• 金额: $ 42.5万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888298
• 关键词: Address; Affect; Bacteria; Bacterial Infections; Binding; Biochemical; CASP1 gene; Caspase; Cells; Chronic; Clinical; Clinical Trials; Complex; Country; Data; Defect; Disease; Disease model; Feedback; Germ-Line Mutation; Gram-Negative Bacteria; Health; Homeostasis; Host Defense; Human; Immune System Diseases; Immune response; Immune system; Immunosuppression; Impairment; Incidence; Income; Infection; Inflammasome; Inflammation; Inflammatory; Inherited; Interleukin-1 beta; Interleukin-18; Link; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Permeability; Phagosomes; Pharmaceutical Preparations; Predisposition; Protein Family; Proteins; Recombinants; Regulation; Research; Resolution; Role; Sepsis; Shock; Signal Induction; Signal Transduction; Toxin; Transgenic Mice; base; cecal ligation puncture; cytokine; cytokine release syndrome; design; effective therapy; immunoreaction; improved; in vivo; inhibitor/antagonist; innate immune mechanisms; macrophage; member; mortality; mouse model; novel; novel therapeutics; particle; pathogen; prevent; public health relevance; recruit; response; sensor; septic; tool; treatment strategy

 DESCRIPTION (provided by applicant) Sepsis is the 10th leading cause of mortality in high-income countries with steadily rising incidence rates, caused by an over-reaction of the immune system to invasive pathogens. Mortality is a consequence of the complex host response with both the initial cytokine storm, as well as secondary immune suppression. Both the canonical and non-canonical inflammasome pathways through activation of caspases-1 and caspase-11 (caspase-4 in humans), respectively, are essential for mediating the responses to cytosolic pathogens and their PAMPS, including LPS, leading to pyroptosis and release of cytokines and danger signals. The canonical pathway is activated by cytosolic PRRs, including NLRP3. Assembly and signaling of the NLRP3 inflammasome is dependent on the PYRIN domain (PYD)-PYD interaction between NLRP3 and the adaptor ASC. The non-canonical pathway responds to cytosolic LPS and Gram-negative bacteria escaping the phagosome with pyroptosis, and engages the canonical NLRP3 inflammasome for cytokine release for host defense. However, defects in termination and uncontrolled activity results in excessive systemic inflammation and is linked to inflammatory and immune diseases. Hereditary mutations in NLRP3 cause Cryopyrinopathies (CAPS), a systemic inflammatory disease, which can be recapitulated in mice. Inflammasome particles are also released by MΦ and act as danger signals to further perpetuate inflammation to bystander cells, and these particles are found in sera in inflammatory disease patients and during bacterial infection and are thought to be responsible for the persistent and chronic responses. Thus, regulation/resolution of inflammasome responses is of utmost importance for maintaining homeostasis, but the molecular mechanisms are poorly understood. We discovered the PYD-only protein (POP)1 and established the POP family of inflammasome inhibitors, which are present in humans, but are lacking from mice and their endogenous functions have not been elucidated. We therefore developed a novel mouse model to study POP1 in vivo. We identified POP1 as a first key regulator for both the canonical and non- canonical inflammasomes as well as the bystander cell response during systemic inflammatory disease, discovered derailed expression of POP1 in human patients, and the objective of this application is therefore to elucidate the molecular mechanism in human and mouse macrophages and in vivo. We expect that the uncovered molecular mechanisms of this inflammasome pathway regulation will be widely applicable to other inflammasomopathies and infections and therefore positively affect human health.