Role of AMP-activated protein kinase in bacterial endophthalmitis

AMP 激活蛋白激酶在细菌性眼内炎中的作用

• 批准号: 9899998
• 负责人: Ashok Kumar
• 金额: $ 38.35万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899998
• 关键词: Ablation; Adenosine Monophosphate; Adopted; Adoptive Transfer; Aging; Anti-Inflammatory Agents; Area; Bacteria; Bacterial Antibiotic Resistance; Bioenergetics; Blindness; Bone Marrow; Cells; Characteristics; Chemicals; Chimera organism; Citric Acid Cycle; Complication; Cyclic AMP-Dependent Protein Kinases; Development; Disease; Disease Progression; Endophthalmitis; Energy Metabolism; Event; Exhibits; Eye Infections; Functional disorder; Genes; Genus Hippocampus; Glycolysis; Goals; Host Defense; Human; Immune; Immune response; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-10; Interleukin-6; Investigation; Knock-out; Knockout Mice; Lead; Light; Link; Mediating; Mediator of activation protein; Metabolic; Metabolism; Microglia; Mitochondria; Modeling; Modification; Molecular; Mus; Myeloid Cells; Natural Immunity; Nature; Nitric Oxide; Operative Surgical Procedures; Oxidative Phosphorylation; PTGS2 gene; PTPRC gene; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Phase; Phenotype; Phosphorylation; Population; Prevalence; Prevention; Production; Protein Kinase; Reporting; Resolution; Retina; Ribonucleosides; Role; STK11 gene; Source; Staphylococcus aureus; Systems Biology; TNF gene; Testing; Therapeutic; Time; Tissues; Toll-like receptors; Trauma; Vision; Visual; Wild Type Mouse; adduct; antimicrobial; bacterial endophthalmitis; cell growth regulation; cell injury; cytokine; disability; immunomodulatory therapies; intravitreal injection; lipid biosynthesis; macrophage; metabolomics; microbial; mitochondrial dysfunction; monocyte; mouse model; neutrophil; new therapeutic target; novel therapeutic intervention; novel therapeutics; pathogen; pathogenic bacteria; protective effect; response; tissue repair; trafficking; transcriptome; upstream kinase

Project Summary The role of myeloid cells such as neutrophils in providing host defense to microbial infections is well- established; however, the contribution of monocytes/macrophages (Mϕ) to the pathophysiology of bacterial endophthalmitis is less clear. Our preliminary studies revealed that Mϕ depletion results in increased inflammatory mediators at the resolution phase, suggesting their involvement in the resolution of endophthalmitis. The Mϕ perform multiple tasks, including sensing pathogens, tissue repair, and, in response to host-derived mediators, they differentiate into distinct functional phenotypes; a feature termed "plasticity". The "classically activated" Mϕ (M1) produce inflammatory cytokines and nitric oxide, contributing to host tissue damage. Conversely, the "alternatively activated" Mϕ (M2) mediate tissue repair through the elimination of damaged cells/tissue and the production of anti-inflammatory molecules to resolve inflammation. Therefore, understanding the mechanisms governing the phenotypic switch of Mϕ can be utilized to develop novel therapeutic strategies. Our transcriptome and metabolomics analyses of the bacteria-infected retina directed us to the identification of adenosine monophosphate-activated protein kinase (AMPK), a metabolic gene, which modulates the infiltrating myeloid cell phenotype in endophthalmitis. We discovered that mice with global deletion (knockout) of AMPKα1 (KO) developed severe endophthalmitis and pathology compared to wild type (WT) mice. Mϕ lacking AMPKα1 maintained a low metabolic state, even in the hyper-inflammatory state. To precisely examine the role of AMPK in myeloid cells, we induced endophthalmitis in myeloid cell specific KO of AMPKα1 (LysM-KO) and observed that LysM-KO displayed exacerbated inflammation and reduced retinal function compared to WT mice, suggesting an essential role of AMPK in myeloid cells in the pathogenesis of bacterial endophthalmitis. Building on these findings, we propose to test our central hypothesis that AMPK exerts protective effects in bacterial endophthalmitis by modulating the polarization of infiltrating monocytes/Mϕ to promote inflammation resolution and that metabolic reprograming is an underlying mechanism of the monocytes/Mϕ phenotype switch. To test our hypothesis, in Aim 1, we will investigate the mechanisms underlying reduced AMPK activity in bacterial endophthalmitis by examining the modification of LKB1 via nitrosylation or chemical adduct formation. Aim 2 tests the hypothesis that AMPKα1 ablation enhances the activation state of myeloid cells and maintains their proinflammatory (M1) state during the resolution phase of the disease. In Aim 3, we will decipher the bioenergetic events, regulated by AMPK in Mϕ, that polarize and maintain their pro-inflammatory nature. The anticipated results of this study will demonstrate that defective AMPK activity in myeloid cells, mainly in monocytes/M impacts the resolution of endophthalmitis via regulation of cellular metabolism. Also, it may provide novel therapeutic targets for the development of anti- inflammatory therapies for endophthalmitis and other microbial infections.

项目总结