Preface

The human body is an intricate and wondrous system, constantly engaged in a delicate balance of maintaining health and combating various threats. Inflammation, a fundamental process of the immune system, plays a critical role in the body's defense against infection and injury. While inflammation is an essential mechanism for maintaining tissue homeostasis, dysregulated or chronic inflammation can lead to the development and progression of numerous diseases. Within the realm of inflammation, the NLRP3 inflammasome has emerged as a captivating protagonist in recent years. This book, “The NLRP3 Inflammasome: An Attentive Arbiter of Inflammatory Response,” delves deep into the intricate workings of this molecular complex and explores its pivotal role in shaping the inflammatory landscape.

Our understanding of the NLRP3 inflammasome has undergone significant advances since its initial discovery. This enigmatic protein complex, comprised of NLRP3 (NOD-like receptor family, pyrin domain-containing 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and pro-caspase-1, acts as a sensor of danger signals within the cell, orchestrating a cascade of events that culminate in the production and release of pro-inflammatory cytokines, particularly interleukin-1β (IL-1β) and IL-18.

“The NLRP3 Inflammasome: An Attentive Arbiter of Inflammatory Response” is a comprehensive exploration of the intricacies surrounding the NLRP3 inflammasome. Through the collaboration of esteemed scientists, researchers, and clinicians, this book seeks to shed light on the various aspects of NLRP3 biology, regulation, and its involvement in a wide array of diseases, ranging from metabolic disorders to neurodegenerative conditions.

In the first chapter, writer Dr. Rashmi Singh, along with her co-authors, has made a significant contribution to the understanding of the role of the NLRP3 inflammasome in airway inflammation and fibrosis. In their research, they have focused on elucidating the mechanisms of NLRP3 inflammasome activation and its impact on respiratory diseases such as asthma. Their work has highlighted the crucial role of NLRP3 in mediating caspase-1 activation and the secretion of proinflammatory cytokines, which contribute to the progression of asthma by promoting excessive inflammation, extracellular matrix accumulation, and airway remodeling. Moreover, they have identified endotoxin (lipopolysaccharide, LPS) as one of the activators of NLRP3, linking environmental factors to the incidence of asthma and allergic diseases. This chapter provides a comprehensive summary of their research findings, shedding light on the mechanisms underlying NLRP3 inflammasome activation and its regulation in asthmatic exacerbations.

In the second chapter, Dr. Sushweta Mahalanobish, along with co-authors Noyel Ghosh and Parames C. Sil, has made a significant contribution to the understanding of the role of NLRP3 inflammasome in pulmonary hypertension (PH). Their research focuses on the progressive pulmonary vasculopathy characterized by increased mean pulmonary arterial pressure, adverse vascular remodeling, and right ventricular failure. They explore the involvement of inflammation as a crucial factor in the onset and development of PH, specifically highlighting the NLRP3 inflammasome as a key mediator in the signaling cascade that regulates PH-associated conditions through inflammatory mechanisms. The activation of NLRP3 and the subsequent release of proinflammatory cytokines IL-1β and IL-18 contribute to adverse consequences on pulmonary vasculature and the onset of PH. The chapter delves into current PH therapies and their limitations and introduces the potential therapeutic targeting of NLRP3 inflammasomes to modulate inflammation in PH pathobiology. The authors provide a comp-

rehensive insight into the role of NLRP3 inflammasome in PH and its implications for future therapeutic interventions.

Dr. Abhinav Kanwal and his team have provided a comprehensive exploration of the modulatory mechanism of the NLRP3 inflammasome in heart diseases. Despite significant advancements in therapy, heart failure remains a leading cause of mortality worldwide. The authors highlight the crucial role of the inflammasome in the progression of various cardiovascular diseases, including heart failure, abdominal aortic aneurysm, atherosclerosis, diabetic cardiomyopathy, hypertension, dilated cardiomyopathy, cardiac remodeling, and calcific aortic valve disease. Specifically, they focus on the NLRP3 inflammasome, a multi-protein signaling platform that tightly regulates inflammatory responses and antimicrobial host defense, leading to the generation of pro-inflammatory cytokines through the activation of caspase-1 and subsequent pyroptosis. By investigating the NLRP3 inflammasome in different cardiovascular diseases, the authors aim to uncover critical disease triggers and endogenous modulators with the aim of developing new therapeutic interventions in the future. The chapter provides a summary of recent literature, emphasizing the activation mechanism of the NLRP3 inflammasome and its implications in the pathophysiology of heart failure, shedding light on this complex and intriguing aspect of heart diseases.

In the fourth chapter, Monika Joon and Manisha Yadav explore the intricate relationship between Mycobacterium tuberculosis (Mtb) and the inflammasome. Mtb is known as a highly successful human pathogen, capable of evading the host immune response through the development of robust effectors. It can survive and multiply within the host's immune system, even in the presence of immune tools meant to eliminate it. Granuloma formation, a compensatory mechanism, offers partial benefits to both the host and the pathogen. While extensive research has been conducted on various mycobacterial virulence factors, the relatively newer concept of inflammasomes requires further investigation. Insights into the inflammasome-Mtb interaction may open up new avenues for the development of host-directed therapy (HDT) strategies to combat TB. By comprehending the intricate dynamics between the inflammasome and Mtb, novel approaches for managing this disease can be explored.

The fifth chapter by Syed Ehtaishamul Haque, Aamir Khan, and Ashif Iqubal deals with an overview of the NLRP3 inflammasome's activation mechanism, its association with cardiovascular complications, and the potential of NLRP3 inhibitors as cardioprotective agents. They highlight the positive correlation between NLRP3 inflammasome activation and various cardiovascular disorders, including hypertension, angina, arrhythmia, cardiac fibrosis, myocardial infarction, and heart failure. By discussing the structural components of the NLRP3 inflammasome and its molecular activation pathway, the authors underline its crucial role in the pathogenesis of cardiovascular diseases. Furthermore, they shed light on promising outcomes from studies exploring NLRP3 inflammasome inhibitors in cardiovascular disorders. Overall, the manuscript underscores the importance of targeting the NLRP3 inflammasome as a potential therapeutic approach for managing and treating cardiovascular diseases.

In the sixth chapter, Sonal Yadav exami nes the role of NLRP3 in protozoan parasitic infections. They discuss the activation of the NLRP3 inflammasome by various protozoan parasites, including Giardia duodenalis, Entamoeba histolytica, Trichomonas vaginalis, Plasmodium species, Trypanosoma cruzi, Schistosomes, Toxoplasma gondii, and Leishmania species. The authors highlight the protective effects of NLRP3 against certain infections, such as Giardia, Trypanosoma cruzi, and Entamoeba histolytica, while also noting its contribution to pathology in Schistosomes and Malaria parasite infections. They emphasize the need for further research to better understand the precise mechanisms and roles of NLRP3 in host defense and inflammatory pathology in parasitic protozoan infections, which could pave the way for the development of innovative treatment strategies.

The seventh chapter by Dr. Adekunle Babajide Rowaiye and his colleagues focu ses on the NLRP3 inflammasome as a target for anti-inflammatory drugs. They highlight the crucial role of the NLRP3 inflammasome in the innate immune response and its association with various inflammation-related diseases. The authors discuss the activation of the NLRP3 inflammasome and the production of proinflammatory cytokines, emphasizing the importance of inhibitory mechanisms to decrease inflammation and inflammasome-mediated cell death. They further explore the potential of targeting signaling molecules along the NLRP3 inflammasome pathway as drug targets for effective inhibition and downregulation of proinflammatory cytokines. The chapter provides insights into the classes of NLRP3 inflammasome inhibitors, their anti-inflammatory effects, and underlying mechanisms of action.

Dr. Agnès Hamzaoui and co-authors, in the eighth chapter, investigate the potential value of sputum levels of Interleukin-38 (IL-38) and NLRP3 inflammasome in severe childhood asthma. Asthma is known to be an inflammatory airway disorder with varying expression of cytokines based on disease severity. The transition from exacerbation to remission involves a complex interplay between inflammatory and anti-inflammatory mediators. The authors focus on the expression of IL-38 and NLRP3 inflammasome in severe asthmatic children. They find that NLRP3 inflammasome is upregulated in severe asthma, while levels of IL-38 are low. The inflammatory profile of severe asthma in children is characterized by the expression of IL-17, IL-32, IL-1β, and NLRP3 inflammasome. This study sheds light on the potential role of IL-38 and NLRP3 inflammasome as biomarkers in severe childhood asthma. It contributes to a better understanding of the inflammatory mechanisms involved in the disease.

The ninth chapter by Lokesh Sharan, Anubrato Pal, Priya Saha, and Ashutosh Kumar expl ores the role of inflammasomes, specifically NLRP1, NLRP3, NLRC4, and AIM2, in inflammation and neuropathic pain. These inflammasomes play a crucial role in the development of autoimmune and metabolic disorders, cancer, and various inflammatory conditions. The activation of inflammasomes is triggered by molecular changes, such as mitochondrial dysfunction, neuroinflammation, lysosomal damage, oxidative stress, sensitization, and disinhibition, leading to the activation of proinflammatory pathways and subsequent development of inflammasome-related neuropathic pain. Among these inflammasomes, NLRP3 has been extensively studied and identified as a key player in neuropathy. This chapter provides an overview of the involvement of inflammasomes, particularly NLRP3, in neuropathic pain. Based on available evidence, targeting inflammasome activity is proposed as a potential cutting-edge approach for the successful treatment of neuropathic pain. The understanding of inflammasome-mediated mechanisms in neuropathic pain may pave the way for the development of novel therapeutic strategies in the future.

The chapters in this book provide in-depth analyses of the mechanisms underlying NLRP3 inflammasome activation, the signaling pathways involved, and the interplay between NLRP3 and other cellular processes. Additionally, the authors delve into the consequences of dysregulated NLRP3 activation, highlighting the implications for disease pathogenesis and potential therapeutic interventions. From the role of NLRP3 in sterile inflammation to its contribution to the pathogenesis of autoimmune disorders, each chapter offers valuable insights into this captivating field of research.

I hope that “The NLRP3 Inflammasome: An Attentive Arbiter of Inflammatory Response” serves as a valuable resource for scientists, clinicians, and students alike, fostering a deeper understanding of the NLRP3 inflammasome and its impact on human health. It is our sincere belief that by unraveling the mysteries surrounding this vigilant arbiter of inflammation, we can unlock novel therapeutic strategies that harness its potential for the betterment of patients worldwide.

I would like to express my sincere gratitude to Mr. Nitin Kumar for his invaluable assistance in the editing and refining of the book. I am also immensely thankful to Ms. Humaira Hashmi, In-charge of the eBook Department, and Ms. Asma Ahmed, Manager of the eBooks Publication Department for her support in publishing this book and Mr. Mahmood Alam, Director of Publications at Bentham Science Publishers, for their unwavering support, encouragement, and assistance. Their contributions have been instrumental in bringing this book to fruition.