The Inflammasome And Its Role In Infections

The inflammasome was first described in 2002 as a molecular complex activating proinflammatory caspases and therefore regulating the maturation and biological activities of cytokines such as IL-1 and IL-18. This finding was substantiated by the identification of several mutations in the cias1 gene, encoding the human NLRP3 protein, responsible for several autoinflammatory disorders such as the Muckle Wells syndrome. Since, the interest for this complex has constantly increased and several inflammasome complexes with different specificities have been described. These inflammasomes sense a wide variety of pathogens and danger signals and are key players in the inflammatory response. With the contributions of leading international experts in the field, this book provides an extensive overview of the current knowledge of inflammasome biology and their role in health and disease.

The term inflammasome was coined over a decade ago to describe the molecular platform activated by pathogens or stressor molecules where inflammatory caspases are triggered and cleavage of IL-1β takes place. Inflammasome regulation is critical for the maintenance of homeostasis: an imbalance in this fine-tuning is responsible for the establishment of infectious, autoimmune, metabolic and neurodegenerative diseases. This book examines the activation and function of inflammasomes during fungal infections; inflammasome involvement in carcinogenesis; and the role of inflammasomes in protozoan infections.

This Methods in Molecular Biology book offers methods for studying inflammasome function, including generation of inflammasome stimuli, monitoring of caspase-1 activity and processing, activation of IL-1β cytokines, plus lab protocols, material lists and tips.

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. Provides comprehensive coverage of the subject of inflammasome biology Authored by leading experts worldwide Provides biological insights that have both health implications and therapeutic potential

"The incidence and prevalence of inflammatory bowel diseases (IBD) have dramatically risen in both developed and developing nations in the last 50 years. While there has been much debate on both the genetic and environmental causes of IBD, it is thought to arise from an abnormal immune response to the commensal intestinal microbiota in susceptible individuals. Recent human and mouse genetic results, as well as functional data from experimental animal models of colitis, have both pointed to a key role of the inflammasome-IL-18 pathway in intestinal homeostasis. The inflammasomes are sensors of microbial/danger signals and are key effectors of the innate inflammatory response. They are scaffolded by intracellular pattern recognition receptors and are required for the activation of caspase-1, an inflammatory protease necessary for the processing of IL-1[beta] and IL-18 into their mature biologically active cytokine forms. We hypothesized that IL-18 is required for the activation and effector functions of specific intestinal cells that initiate downstream epithelial repair and host defense mechanisms. In an experimental model of infectious colitis using Citrobacter rodentium infection, we determined that Il18-/- mice were more susceptible to C. rodentium infection compared to wild-type (WT) mice. However, infections using Rag1-/- and Rag1-/-/Il18-/- mice showed a reverse phenotype; Rag1-/- mice showed increased disease phenotypes compared to Rag1-/-/Il18-/- mice. Bone marrow chimera experiments using WT and Il18r-/- mice further demonstrated that IL-18 signaling in the stromal or radio-resistant compartment is vital for host resistance. Altogether, these results suggest that IL-18 plays a dual role in both the innate and adaptive immune responses during an infection that is crucial to control the severity of the disease. The future identification of IL-18-responsive stromal cells as well as the exploration of the role of IL-18 signaling and downstream effector functions of target cells in intestinal homeostasis will further allow us to assemble a more comprehensive picture of interactions between IL-18 and mucosal stromal cells after injury or infection, and how these pathways are able to affect both the generation and progression of the disease." --

Inflammasomes are cytosolic, multimeric protein complexes formed within certain host cells, including macrophages, upon detection of pathogen-associated molecular patterns or danger-associated molecular patterns by members of the NOD-like receptor (NLR) family. Inflammasomes are important for the host defence against pathogens, including Salmonella enterica serovar Typhimurium (S. Typhimurium). Formation of the inflammasome is critical for host defence because it facilitates caspase-1-dependent processing of the proinflammatory cytokines pro-IL-1[beta] and pro-IL-18 into their mature forms. The inflammasome also drives a rapid form of macrophage cell death known as pyroptosis, which may be important for bacterial clearance.

Our gut is colonized by numerous bacteria throughout our life, and the gut epithelium is constantly exposed to foreign microbes and dietary antigens. Thus, the gut epithelium acts as a barrier against microbial invaders and is equipped with various innate defense systems. Resident commensal and foreign invading bacteria interact intimately with the gut epithelium and can impact host cellular and innate immune responses. From the perspective of many pathogenic bacteria, the gut epithelium serves as an infectious foothold and port of entry for disseminate into deeper tissues. In some instances when the intestinal defense activity and host immune system become compromised, even commensal and opportunistic pathogenic bacteria can cross the barrier and initiate local and systematic infectious diseases. Conversely, some highly pathogenic bacteria, such as those highlighted in this book, are able to colonize or invade the intestinal epithelium despite the gut barrier function is intact. Therefore, the relationship between the defensive activity of the intestinal epithelium against microbes and the pathogenesis of infective microbes becomes the basis for maintaining a healthy life. The authors offer an overview of the current topics related to major gastric and enteric pathogens, while highlighting their highly evolved host (human)-adapted infectious processes. Clearly, an in-depth study of bacterial infectious strategies, as well as the host cellular and immune responses, presented in each chapter of this book will provide further insight into the critical roles of the host innate and adaptive immune systems and their importance in determining the severity or completely preventing infectious diseases. Furthermore, under the continuous threat of emerging and re-emerging infectious diseases, the topic of gut-bacteria molecular interactions will provide various clues and ideas for the development of new therapeutic strategies.

DNA Sensors and Inflammasomes, Volume 625, the latest release in the Methods in Enzymology series, continues the legacy of this premier serial with quality chapters authored by leaders in the field. New sections in this release include Phosphorylation and dimerization of STING and IRF3, cGAS enzymology, Synthesis and identification of immuno-stimulatory CDNs, Tracking cGAS activity/ cGAMP formation using SPR/NMR, Using an enzyme coupled assay to track cGAS activity under steady states, Tracking the polymerization of DNA sensors, inflammasome receptors, and downstream signaling partners using FRET, NLRC4 structure, Tracking TREX1 activity, DNA association and dissociation kinetics of PARP1, and more.

There are millions of people who experience issues related to brain health—depression, attention issues, anxiety, forgetfulness, fatigue, and even chronic pain—yet can’t figure out what’s causing their problems and can’t find any relief. They may have seen a myriad of doctors, many of whom do not take their complaints seriously, or worse, turn to the easy, often inappropriate fix of antidepressants or anti-anxiety medications. Traditional medications, supplements, or other therapies haven’t worked. No matter what their age—from children to teens or seniors—people and their loved ones are frustrated, scared, and confused by their continued poor health. Countless others display severe psychiatric symptoms that seem to come out of nowhere, ranging from tics, obsessive-compulsive behaviors and anxiety, to depression, bipolar-like mood swings, and even borderline personality disorder and suicidal ideas. Sometimes, the people affected are the only ones that notices a change to the way they think or feel, and they suffer in silence. Or, they reach out to try to get help, and are all too frequently misdiagnosed. David Younger, a world-renowned physician, provides relief to these patients and their families. His diagnostic techniques and treatment protocols will help readers identify the true cause of their symptoms and put them on a clear path to healing so they no longer feel unbalanced, out of control, forgetful, and exhausted. The Autoimmune Brain connects common brain health symptoms to the changes in the immune system, and particularly bacterial, viral, and parasitic infections. Younger explains his groundbreaking research and adds a new component: how traumatic stress (whether physical or emotional) and genetics affects this same triad as inextricable factors in initiating disease and brain health symptoms. In fact, a change in personality, behavior, coping style, and one’s emotional state may be the first clue that there is a health problem brewing somewhere else in the body. Readers will find new answers to troubling conditions, including: Alzheimer’s disease; Anxiety; Arthritis; Autism; Autonomic disturbances; Bacterial and viral infections; Bipolar Disorder; Cancer; Celiac disease and gluten intolerances; Chronic Fatigue Syndrome (now referred to as Systemic Exertion Intolerance Disease); Chronic Pain; Dementia; Depression; Endocrine Disorders; Immune modulatory therapy using IVIg; Lyme disease and co-infections; Mast cell activation syndrome; Medical cannabis; Obsessive Compulsive Disorder; Orthostatic hypotension; Peripheral Neuropathy; Porphyria; Post-Traumatic Stress Disorder; and Postural orthostatic tachycardia.