title: Inflammasome, mTORC1 activation, and metabolic derangement contribute to the susceptibility of diabetics to infections.
abstract: The mechanisms leading to higher risks of infection in diabetics remain unknown despite recent advances in the understanding of associated immunological and metabolic aberrations. Hyperglycemia and hyperlipidemia in diabetics not only contribute to altered metabolism but glucose and free fatty acids can directly activate inflammation and the production of the proinflammatory cytokine interleukin 1β (IL-1β). Long-chain saturated fatty acids activate toll-like receptor 4 (TLR4), generating diacylglycerol and activating protein kinase C to upregulate the Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway. High glucose uptake switches cell metabolism from oxidative phosphorylation to glycolysis and deactivates AMP-activated protein kinase (AMPK), a critical sensor of nutrient and cellular energy, leading to mTORC1 activation. A deleterious consequence of mTORC1 activation is the suppression of autophagy which is a catabolic process for the lysosomal degradation of damaged organelles, protein aggregates and intracellular pathogens. In addition, high glucose concentration and fatty acids independently activate inflammasome, an intracellular multi-protein complex that promotes the proteolytic activation of caspase 1, leading to the processing and secretion of IL-1β. Other caspases induced by inflammasome can trigger apoptotic cell death. A common upstream signal for the activation of inflammasome and mTORC1 is oxidative stress, which generates reactive oxygen species (ROS) from dysregulated mitochondria. Increased flux of glucose and lipids activates stress kinases, enhances electron transport, and generates ROS in mitochondria. Mitochondrial stress arising from increased mitochondrial respiration and permeability damages mitochondria, activates caspases, which then induce apoptosis via the intrinsic cell death pathway releasing mitochondrial DNA. Normally apoptosis is down-regulated by autophagy as autophagy removes damaged organelles as a result of danger and stress signals. However, in diabetics, hyperactivation of mTORC1 disrupts the host autophagic degradation of microbes and damaged mitochondria which in turn exacerbates inflammasome activation and alters cell resistance to infection. Recognition of viral lipids and bacterial components by host cell pattern recognition receptors including TLR activates NFκB and stress kinase c-jun N-terminal kinase (JNK) signaling. The transcription factor NFκB and JNK independently induce inflammatory cytokines, chemokines, and further activate inflammasome. The convergence of inflammasome and mTORC1 activation with metabolic stress and vascular dysfunction in diabetics prevents pathogen clearance and contributes to an increased risk of infection.
authors.affiliation: Department of Immunology, Molecular Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702-5011, United States. Electronic address: Teresa.Krakauer.civ@mail.mil.
authors.forename: Teresa
authors.initials: T
authors.lastname: Krakauer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017209:Apoptosis; D001343:Autophagy; D048909:Diabetes Complications / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007239:Infections / Q000150:complications / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D000076222:Mechanistic Target of Rapamycin Complex 1; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D008055:Lipids; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose