Inflammasome Biology: Fundamentals, Role in Disease States, and Therapeutic Opportunities

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Inflammasome Biology: Fundamentals, Role in Disease States, and Therapeutic Opportunities is a complete reference on the role of inflammasomes in health and disease. Sections cover the different types of inflammasomes, including cellular signaling, structural and evolutive aspects, overview the role of inflammasomes in key diseases, microbial infections and human body systems conditions, cover the interplay between Inflammasomes and cell death processes, and discuss current therapeutic opportunities driven by inflammasome research, including targeting, blocking and inhibiting the development of inflammasomes through both synthetic and natural compounds. This book is the perfect reference for cell biologists, immunologists and research clinicians to understand the foundations of inflammasomes and explore the therapeutic opportunities they present. Pharma researchers may also find this reference invaluable in devising new approaches to developing anti-inflammatory drugs. Front Cover Inflammasome Biology Inflammasome Biology: Fundamentals, Role in Disease States, and Therapeutic Opportunities Copyright Contents Contributors Contributors 1 - Fundamentals of inflammasome biology 1 - The inflammatory process at the cellular level 1. Introduction 2. At the dawn of inflammation 3. Detection and integration of inflammatory signals 4. Inflammatory cells and inflammatory mediators 5. Inflammation is an energy-consuming process 6. Resolution (or lack of resolution) of inflammation 7. Conclusions Acknowledgments References 2 - Inflammasome formation and triggers 1. The inflammasome platform assembles in response to various triggers 2. Inflammasome sensors predominantly belong to NLR and ALR receptor families 3. Adaptor ASC augments inflammation 4. Caspase-1 processes proinflammatory cytokines and gasdermin D 5. NLRP3 inflammasome 6. NAIP/NLRC4 inflammasome 7. NLRP6 inflammasome 8. NLRP1 inflammasome 9. CARD8 inflammasome 10. AIM2 inflammasome 11. Pyrin inflammasome 12. Conclusions Acknowledgments References 3 - The NLRP1 and CARD8 inflammasomes 1. NLRP1 and CARD8 domain architecture 2. NLRP1 and CARD8 activation by proteolytic cleavage 3. NLRP1 activation by pathogen-associated E3 ligases 4. Activation of NLRP1 by dsRNA 5. Activation of NLRP1 through ATP depletion 6. NLRP1 recognition of Toxoplasma infection 7. Regulation of NLRP1 by DPP8 and DPP9 8. Disease-associated mutations in NLRP1 9. Unresolved questions Acknowledgments References 4 - Cellular signaling, molecular activation, and regulation of the NLRP3 inflammasome 1. Introduction 2. NLRP3 priming 2.1 Transcriptional priming 2.2 NLRP3 PTMs induced by a priming stimulus (licensing) 2.3 NLRP3 PTMs induced by an activating stimulus 3. Canonical NLRP3 activation 3.1 Ion flux 3.2 Organelle dysfunction 4. Other pathways of NLRP3 activation 4.1 Noncanonical NLRP3 activation 4.2 Alternative NLRP3 activation 5. Conclusion References 5 - Cellular signaling, molecular activation, and regulation of the NLRP6 inflammasome 1. Introduction 2. NLRP6 expression 3. NLRP6 activation 4. Inflammasome-dependent and inflammasome-independent functions of NLRP6 5. NLRP6 in host defense 6. NLRP6 in epithelial barrier integrity 7. NLRP6 and microbiota 8. NLRP6 in human diseases 9. Concluding remarks References 6 - Molecular regulation of NAIP/NLRC4 inflammasomes 1. NAIP/NLRC4 inflammasomes 2. Molecular mechanisms involved in canonical NAIP/NLRC4 inflammasome assembly 3. Molecular mechanisms involved in the noncanonical activation of NAIP/NLRC4 4. Role of NAIP/NLRC4 in host defense against infections 5. Role of NLRC4 in inflammatory pathologies 6. NAIP/NLRC4 in cancer 7. Conclusions and future directions References 7 - Cellular signaling, molecular activation, and regulation of the AIM2 inflammasome 1. Introduction 2. Mechanism of AIM2 inflammasome assembly 3. AIM2-mediated recognition of infection and self-DNA 3.1 Recognition of bacterial infection 3.2 Recognition of viral infection 3.3 Recognition of other infections 3.4 Recognition of self-DNA 4. Positive and negative regulation of the AIM2 inflammasome 4.1 Positive regulation of AIM2: interferons that facilitate, not interfere 4.2 Negative regulation of AIM2 5. Conclusions References 8 - Molecular activation, cellular signaling, and regulation of the Pyrin inflammasome 1. Introduction 2. Pyrin structure 3. Pyrin is a guard of RhoA GTPases 4. Pyrin activation during bacterial infections 5. The regulation of Pyrin inflammasome 5.1 Transcriptional regulation 5.2 Posttranslational regulation 5.3 Regulation by the autophagy machinery 6. Pyrin in autoinflammatory diseases 6.1 Familial Mediterranean fever 6.2 Pyrin-associated autoinflammation with neutrophilic dermatosis 6.3 Pyogenic sterile arthritis pyoderma gangrenosum and severe acne (PAPA) syndrome 6.4 Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia 6.5 Cdc42-associated severe autoinflammatory diseases 6.6 Mevalonate kinase deficiency 6.7 Colitis and colorectal cancer 7. Conclusions Acknowledgments References 9 - Cellular signaling, molecular activation, and regulation of the noncanonical inflammasome 1. Introduction 2. Noncanonical inflammasome activation 3. Cofactors regulating noncanonical inflammasome activation 4. Noncanonical inflammasome assembly 5. Alternative activation of the noncanonical inflammasome 6. Regulation and evasion of the noncanonical inflammasome 7. Concluding remarks Funding References 10 - Cellular signaling, molecular activation, and regulation of auto-active inflammasomes: Insights from disease-a ... 1. Introduction 2. Protein structure 3. Pyrin-associated autoinflammatory disease 4. Familial Mediterranean fever 5. Pyrin-associated dominant diseases 6. Pyrin-associated complex diseases 7. NLR-associated diseases 8. NLRP1-associated diseases 9. NLRP3-associated diseases 10. NLRP3-germline variants–associated diseases 11. NLRP3-somatic variants–associated diseases 12. NLRP3-common variants–associated diseases 13. NLRC4-associated diseases 14. NLRP7-associated diseases 15. NLRP12-associated diseases 16. Conclusion References Links 11 - Autophagy and the inflammasome 1. Introduction 2. Inflammasome 3. Autophagy 4. Autophagy modulates inflammasome activation 4.1 Mitophagy inhibits inflammasome activation 4.2 Autophagy limits inflammation by removing components of the inflammasomes 4.3 Autophagy mediates IL-1β secretion 4.4 Inflammasome regulation of autophagy 5. Sepsis 6. Conclusions and further directions References Further reading 12 - Inflammasome effector functions: a Tale of Fire and Ice 1. Introduction 2. NLRP3 3. NLRP1 4. AIM2 5. NLRC4/NAIP 6. Conclusion References 13 - Inflammatory caspases 1. Introduction 2. Domain structure of inflammatory caspases 3. CARD-mediated dimerization of caspase catalytic domains induces basal activity 4. Autoproteolytic cleavage of the interdomain linker yields fully active inflammatory caspases 5. Substrates recognition by inflammatory caspases 6. Regulation of inflammatory caspases on inflammasomes 7. Regulation of inflammatory caspases-1CARD filament formation 8. Concluding remarks Acknowledgments References 14 - Structural aspects of inflammasomes forming NOD-like receptors 1. Introduction 2. Inflammasome-forming NOD-like receptors 3. NOD-like receptors are STAND family ATPases 4. Sequence motifs in the NOD module 5. Domain composition and architecture of NOD-like receptors 6. Conformational states of NLRs from inactive to active 7. Structures of inactive inflammasomal proteins 8. Structure of active inflammasome-forming NLRs 9. Downstream effectors of the NLR nucleation seed 10. Conclusions Acknowledgments References 15 - Evolutive aspects of inflammasomes 1. Introduction 2. Evolution of inflammasome-related genes in mammals and teleosts 2.1 NLR family with a pyrin domain 2.2 ASC 2.3 Inflammasome effector cysteine-aspartic proteases (caspases) 3. Functional evolution of the CASP1 3.1 Cleavage of IL-1β 3.2 Cleavage of effector molecules (GSDM family) for pyroptosis 4. Conclusions References 2 - Inflammasome role in disease processes 16 - The inflammasome in cardiovascular diseases 1. Introduction 2. Atherosclerosis 3. Ischemic heart disease 4. Inflammatory heart disease 5. Dilated cardiomyopathy 6. Heart failure 7. Peripheral arterial disease and venous thromboembolism 8. Acute versus chronic cardiovascular diseases 9. Conclusions Conflict of interest statement References 17 - Inflammasome implications in metabolic disorders 1. Introduction 2. Obesity, diabetes, and related comorbidities 2.1 Obesity and diabetes 2.2 Comorbidities 2.2.1 Cardiovascular diseases 2.2.2 Gastrointestinal dysfunctions 2.2.3 Cognitive dysfunctions 3. Atherosclerosis 4. Nonalcoholic fatty liver disease 5. Conclusions and future perspectives References 18 - The inflammasome in stroke 1. Epidemiology, risk factors, and types of stroke 2. Stroke pathophysiology 3. Molecular events taking place after stroke 4. Inflammasome activation in stroke 5. Inflammasomes involved in the innate immune response after stroke 5.1 The NLRP1 inflammasome 5.2 The NLRP3 inflammasome 5.3 The AIM2 inflammasome 5.4 The NLRC4 inflammasome 6. The inflammasome after stroke in humans 7. Therapeutic targeting of the inflammasome after stroke 8. Conclusions References 19 - Inflammasome and neurodegenerative diseases 1. Introduction 2. Inflammasome, a double-edged sword NLRP3, the predominant inflammasome 4. Inflammasome in Alzheimer's disease 5. Inflammasome activation in PD 6. Inflammasome activation in ALS 7. Conclusion Funding References 20 - Inflammasomes in cigarette smoke- or ozone-induced lung diseases 1. Introduction 2. Cigarette smoke–induced inflammation and COPD 2.1 The NLRP3 inflammasome in COPD 2.2 Gasdermin D and pyroptosis implication in COPD 2.3 AIM2 inflammasome in COPD 3. Ozone-induced inflammation, COPD, and fibrosis 3.1 The NLRP3 inflammasome in COPD inflammation induced by ozone exposure 3.2 Ozone-induced interstitial lung diseases and idiopathic pulmonary fibrosis 4. Conclusions Acknowledgments Authors' contribution Funding References 21 - Inflammasomes and their regulation in oral diseases 1. Introduction 2. Inflammasomes in periodontal disease 3. Inflammasome modulation in periodontal disease 4. Inflammasomes in pulpal diseases 5. Inflammasome modulation in pulpal diseases 6. Inflammasomes in oral cancer 7. Inflammasome modulation in oral cancer 8. Conclusion and future perspectives References 22 - Inflammasome-induced inflammation and fibrosis in liver 1. The NLRP3 inflammasome in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis 2. The NLRP3 inflammasome in alcoholic liver disease 3. The NLRP3 inflammasome in acetaminophen and toxin-induced acute liver failure 4. The NLRP3 inflammasome in autoimmune and viral hepatitis 5. The NLRP3 inflammasome in hepatocarcinogenesis NLRP1, NLRP6, NLRC4, AIM2, and noncanonical inflammasome in liver disease References 23 - Inflammasomes in sepsis 1. Introduction 1.1 Definition of sepsis 1.2 Early recognition 1.3 Diagnosis 2. Clinical consequences of sepsis and clinical management 2.1 Antibiotic treatment and source control 2.2 Hemodynamic resuscitation 2.3 Ventilation 2.4 Other clinical manifestations and therapies 3. Inflammatory response during sepsis 3.1 Physiopathology of the hyperinflammatory response in sepsis 3.2 Physiopathology of immunosuppression in sepsis 3.3 Animal models of sepsis 4. The role of inflammasomes in sepsis 4.1 NLRP3 inflammasome 4.1.1 Non-canonical inflammasome activation 4.2 Other inflammasomes 5. Use of inflammasomes in the prognosis of septic patients Acknowledgments References 24 - The Inflammasome in viral, bacterial, and fungal infections 1. NLRP1 inflammasome in infection 2. Activation of CARD8 inflammasome by the human immunodeficiency virus 3. NLRP3 inflammasome activation in infection 4. NLRC4 inflammasome triggering during infections 5. Other NLRs in infection 6. AIM2 and pyrin inflammasomes during infection 7. The noncanonical inflammasome during infection 8. Concluding remarks References 25 - Autoinflammatory disorders 1. Autoinflammation and monogenic human autoinflammatory disorders 2. Inflammasomopathies 2.1 NLRP3 inflammasome-related diseases 2.2 NLRC4 inflammasome-related diseases 2.3 Pyrin inflammasome-related diseases 2.4 Mevalonate kinase deficiency 2.5 PSTPIP1-related diseases 2.6 NLRP1 inflammasome-related diseases 3. IL-1-mediated, noninflammasome-related autoinflammatory disorders 3.1 Deficiency of IL-1 receptor antagonist 4. Monogenic type I interferonopathies 4.1 Aicardi–Goutières syndrome 4.2 STING-associated vasculopathy with onset in infancy syndrome 4.3 CANDLE syndrome 5. Deficiency of adenosin deaminase 2 (DADA2) 6. Disorders associated with aberrant TNF or NF-κB signaling pathways 6.1 TNF receptor-associated periodic syndrome 6.2 Blau syndrome 6.3 Haploinsufficiency of A20 6.4 VEXAS syndrome 7. Inflammatory actinopathies 8. Others References 26 - The inflammasome in graft-versus-host disease Acknowledgment Author contributions References 27 - Canonical and noncanonical Inflammasomes in kidney disease 1. Introduction 2. Canonical inflammasome activation 3. Noncanonical inflammasome activation 4. Inflammasomes and kidney injury 4.1 Acute kidney injury 4.2 Chronic kidney disease 5. Other inflammasomes in kidney injury 5.1 AIM2 5.2 NLRC4 5.3 NLRC5 6. Conclusions Acknowledgments References 28 - Inflammasomes and cancer 1. Introduction 1.1 Inflammasomes 1.2 Cancers 2. NLRP1 inflammasome and cancer 3. NLRP3 inflammasome and cancer 3.1 Protumor role of NLRP3 inflammasome 3.1.1 NLRP3 inflammasome in cancer cells affects cancer cell viability, proliferation, and migration 3.1.2 NLRP3 inflammasome in the tumor microenvironment affects cancer cell viability, proliferation, and migration 3.1.3 NLRP3 inflammasome in cancer cells affects immune response 3.1.4 NLRP3 inflammasome in the tumor microenvironment affects immune response 3.2 Antitumor role of NLRP3 inflammasome 4. NLRP6 inflammasome and cancer 5. NLRP12 inflammasome and cancer 6. NLRC4 inflammasome and cancer 7. AIM2 inflammasome and cancer 8. Downstream effectors of inflammasomes and cancer 9. Therapeutic perspectives 10. Conclusions Funding Conflicts of Interest References 29 - Inflammasomes in the pathobiology of degenerative retinopathies 1. The organization of the retina 2. The retinal immune system 3. Oxidative stress and the retina 4. Canonical and noncanonical inflammasomes 5. Age-related macular degeneration 6. Dry age–related macular degeneration and the inflammasome 7. Neovascular age–related macular degeneration and the inflammasome 8. The inflammasomes in diabetic retinopathy 9. Inherited retinal degenerations and the inflammasome 10. Therapeutic directions References 3 - Inflammasome cross talk in cell death 30 - Regulation of pyroptosis by inflammasomes 1. Introduction 2. Gasdermin activation and gasdermin pore properties 3. Cytokines and alarmins release during pore formation and pyroptosis 4. Mechanisms to prevent GSDM-mediated pyroptosis 5. Gasdermin regulation by reactive oxygen species production 6. Gasdermin activation by other proteases References 31 - Crosstalk between necroptosis and the inflammasome 1. Proteins that modulate necroptosis 1.1 Receptor-interacting protein kinase 3 1.2 Receptor-interacting protein kinase 1 1.3 Mixed-lineage kinase domain-like protein 1.4 TNF receptor associated factor 2/5 1.5 Cellular inhibitor of apoptosis 1 and 2 1.6 TRADD 1.7 FADD 1.8 Cellular FLICE-like inhibitory protein 1.9 Caspase-8 2. Molecular mechanisms of necroptosis and necrosome formation 3. Interaction of necroptosis with the inflammasome 4. Importance of necroptosis and inflammasome crosstalk in mediating host responses to pathogens 5. Potential role for mitochondria in mediating necroptosis and inflammasome crosstalk 6. Conclusions References 32 - Apoptosis and inflammasome regulation 1. Introduction 2. Extrinsic and intrinsic apoptosis pathways 3. Pyroptosis: programmed necrosis induced by inflammasomes and gasdermin family members 4. Links between apoptosis and pyroptosis 4.1 Direct cleavage of GSDMD by caspase-8 4.2 GSDMD and pannexin-induced NLRP3 activation 4.3 GSDME activation by caspase-3/-7 4.4 Gasdermin activation by granzymes 4.5 Activation of apoptosis by inflammatory caspases 5. Conclusions and outlook Acknowledgments References 33 - Inflammasomes as integral components of PANoptosomes in the regulation of cell death 1. Introduction 2. Regulation of pyroptosis by inflammasomes 3. Inflammasomes at the junction of innate immune cell death crosstalk 4. Role of inflammasomes in PANoptosis 5. Implications of PANoptosis in disease treatment 6. Summary and remaining questions Acknowledgments Conflict of interest statement References 34 - Regulation of neutrophil NETosis by inflammasome 1. Introduction 2. The inflammasome 3. NETosis mechanisms 4. NETosis and inflammasome in disease 5. NET-mediated inflammasome activation 6. Pharmacological inhibition of inflammasome-mediated NETosis 7. Conclusion and perspectives Funding References 4 - Therapeutic opportunities 35 - Therapeutic opportunities targeting the NLRP3 inflammasome 1. Inflammasomes as therapeutic targets 2. Targeting NLRP3 priming 3. Targeting NLRP3 activation 4. Targeting ASC, caspase-1, and gasdermin D 5. Targeting downstream effector functions 6. NLRP3 agonism 7. Conclusions References 36 - Development of selective NLRP3 inflammasome inhibitors 1. Introduction 2. Sulfonylurea and sulfonylurea-derived NLRP3 inhibitors 3. Benzensulfonamide derivatives as NLRP3 inhibitors 4. Acrylic acid derivatives 5. Other chemotypes NLRP3 inhibitors 6. Concluding remarks and future perspectives References 37 - Therapeutic targeting of inflammasome signaling by blocking interleukin-1 1. Introduction 2. Interleukin-1 3. IL-1 inhibitors 4. IL-1 receptor antagonism 4.1 Anakinra 4.2 Isunakinra (EBI-005) 4.3 AMG 108 (MEDI8968) 4.4 Nadunolimab (CAN04) 5. IL-1 decoy receptors 5.1 Soluble IL-1R1 and IL-1R2 5.2 Rilonacept (IL-1 trap) 6. Anti-IL-1 antibodies 6.1 Canakinumab 6.2 Gevokizumab (XOMA 052, VPM087) 6.3 LY2189102 6.4 Bermekimab (MAPp1, Xilonix, JnJ-77474462) 6.5 Lutikizumab (ABT-981) 7. Safety considerations for IL-1 blockers 8. Conclusions References 38 - Multiinflammasome inhibitors Author disclosures 1. Introduction 2. The structure of the ASC: necessary knowledge for the development of pan-inflammasome inhibitors 3. ASC modulation as a strategy for multiinflammasome inhibitors 3.1 Antibodies 3.2 Peptides 3.3 Small molecules 4. Endogenous inflammasome modulators 5. Posttranslational modulation of ASC-mediated inflammasome activation 6. Therapeutic indications for multiinflammasome inhibitors 6.1 Neurodegenerative disorders 6.2 Cardiovascular diseases 6.3 Autoimmune diseases 6.4 Cancer 6.5 Metabolic diseases 6.6 Sepsis 6.7 Viral infections 7. Conclusions References Index A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Back Cover