Role of NLRP3 Inflammasome in Airway Inflammation and Fibrosis
Page: 1-21 (21)
Author: Anju Jaiswal, Asha Kumari and Rashmi Singh*
DOI: 10.2174/9789815223941124010003
PDF Price: $15
Abstract
The NLRP3 inflammasome is a critical component of the innate immune
system that mediates caspase-1 activation and the secretion of proinflammatory
cytokines IL-1β/IL-18 in response to microbial infection and cellular damage.
Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain
3 (NLRP3), one of the members of the NLR family, consists of NLRP3, the adaptor
molecule, apoptosis-associated speck-like protein containing a caspase and recruitment
domain (ASC) and an inflammatory caspase-1 that causes excessive inflammasome
activation in respiratory diseases like asthma and could exacerbate the progression of
asthma by considerably contributing to ECM accumulation and airway remodeling.
NLRP3 is closely associated with airway inflammation and asthma exacerbations as
endotoxin (lipopolysaccharide, LPS) is one of its activators present in the environment.
Asthma is a complex immunological and inflammatory disease characterized by the
presence of airway inflammation, airway wall remodeling and bronchial
hyperresponsiveness (BHR). Symptomatic attacks of asthma can be caused by a myriad
of situations, including allergens, infections, and pollutants, which cause the rapid
aggravation of respiratory problems. The presence of LPS in the environment is
positively correlated with the incidence of asthma and allergic diseases. In this chapter,
we summarize our current understanding of the mechanisms of NLRP3 inflammasome
activation by multiple signaling events in asthmatic exacerbations and their regulation.
NLRP3 Inflammasome: A Novel Mediator in Pulmonary Hypertension
Page: 22-37 (16)
Author: Sushweta Mahalanobish, Noyel Ghosh and Parames C. Sil*
DOI: 10.2174/9789815223941124010004
PDF Price: $15
Abstract
Pulmonary hypertension (PH) is marked by elevated mean pulmonary
arterial pressure, unfavorable vascular remodeling and right ventricular failure. Current
enormous amounts of clinical and preclinical data suggest the role of inflammation as a
crucial factor for PH onset and development by modulating both innate and adaptive
immune responses. In this context, NLRP3 inflammasome appears as a key step in the
signaling cascade that negatively regulates various PH-associated conditions by
inducing inflammatory outbursts. The activation of NLRP3 by pathogen-associated
molecular pattern molecules/damage-associated molecular pattern molecules and
caspase-1 mediated release of proinflammatory cytokines IL-1β and IL-18 are the key
molecular events associated with NLRP3 inflammasomal pathway. Released IL-1β and
IL-18 bring about adverse consequences on the pulmonary vasculature and the
resulting onset of PH. Within this section, we will provide an in-depth understanding of
present pulmonary hypertension (PH) treatments and their shortcomings. We will also
discuss the contribution of NLRP3 inflammasomes in promoting inflammation within
the context of PH pathobiology, as well as explore potential therapeutic approaches to
target them.
Modulatory Mechanism of NLRP3 Inflammasome in Heart Diseases: “An Enigma Wrapped in a Riddle”
Page: 38-56 (19)
Author: Anchal Arora, Ravinder Sharma, Navjot Kanwar, Vikas Gupta, Gunpreet Kaur, Parveen Bansal and Abhinav Kanwal*
DOI: 10.2174/9789815223941124010005
PDF Price: $15
Abstract
Despite breakthroughs in therapy over the prior two decades, heart failure is
considered the foremost cause of mortality globally. The inflammasome plays a pivotal
role in the advancement of heart failure, abdominal aortic aneurysm, atherosclerosis,
diabetic cardiomyopathy, hypertension, dilated cardiomyopathy, cardiac remodeling
and calcific aortic valve disease. The NLRP3 inflammasome is a crucial multi-protein
signaling platform that tightly regulates inflammatory responses. It regulates
antimicrobial host defense, which causes pyroptosis through caspase-1 activation by
the eventual production of pro-inflammatory cytokines. The investigation of the
NLRP3 inflammasome in various cardiovascular diseases may reveal critical disease
triggers and endogenous modulators, leading to the development of new therapeutic
interventions in the future. The target of this chapter is to summarise the recent
literature describing the activation mechanism of the NLRP3 inflammasome by
implicating different inflammatory pathways in the pathophysiology of heart failure.
TB and Inflammasome: A Complex Relationship
Page: 57-71 (15)
Author: Monika Joon and Manisha Yadav*
DOI: 10.2174/9789815223941124010006
PDF Price: $15
Abstract
The reputation of Mycobacterium tuberculosis (Mtb) as one of the most
successful human pathogens has been corroborated bysignificant experimental and
clinical evidence. It infects the human host for long enough to co-evolve with the host,
developing a robust repertoire of effectors to evade the immune response of the host. It
has the capability to survive and multiply inside the very tools of the host immune
system that are employed to eradicate it. Granuloma is a classical structure formed as a
compensatory step in which both the host and the pathogen benefit partially. While a
lot of mycobacterial virulence factors like cell wall envelope components, secreted
proteins and dormancy regulon have been researched extensively, the comparatively
newer concepts of inflammasomes need much attention. This chapter is an attempt to
understand the complex relationship between the inflammasomes and Mtb in light of
recent studies. With the emerging problems of drug resistance in the treatment of Tb,
understanding the relationship between inflammasome and Mtb may present newer
avenues in the development of host-directed therapy (HDT) strategies for combating
Tb .
Mechanism of NLRP3 Activation, Associated Cardiovascular Complications and Update on its Inhibitors Acting as Cardioprotective Agents
Page: 72-95 (24)
Author: Syed Ehtaishamul Haque*, Aamir Khan and Ashif Iqubal
DOI: 10.2174/9789815223941124010007
PDF Price: $15
Abstract
Cardiovascular disorders (CVDs) are a major healthcare issue worldwide
and are accountable for significant mortality and morbidity. Despite advancements in
cellular, molecular, physiological and pathological understanding, a comprehensive
understanding of CVDs is still lacking. Hence, a better understanding of pathological
changes is needed to develop a potential cardioprotective agent. In recent times,
NLRP3 inflammasome has been extensively studied in various disease conditions,
including CVDs. The activation of NLRP3 inflammasome has been found to be
positively correlated with various CVDs, such as hypertension, angina, arrhythmia,
cardiac fibrosis, myocardial infarction, heart failure, etc. Moreover, a number of
NLRP3 inflammasome activators have been explored for their role in CVDs, and the
outcomes of these studies are found to be promising. Therefore, in the present
manuscript, we have discussed the structural component of NLRP3 inflammasome, its
molecular mechanism of activation, and the outcome of various NLRP3 inflammasome
inhibitors in CVDs. We found that NLRP3 inflammasome is an indispensable player of
pathogenesis in CVDs, and thus, targeting this inflammasome can be an effective
approach for managing and treating these diseases.
Role of NLRP3 in Protozoan Parasitic Infections
Page: 96-118 (23)
Author: Sonal Yadav, Harpreet Kaur, Rakesh Singh Dhanda and Manisha Yadav*
DOI: 10.2174/9789815223941124010008
PDF Price: $15
Abstract
Nod-like receptors (NLRs) and the inflammasome complex have significant
roles in regulating the innate immune system against bacterial and viral pathogens and
have attracted significant attention to their role in protozoan infections. Several
parasitic protozoan pathogens are the most prevalent that cause severe morbidity and
pose a significant health burden. In the present article, we discussed the most common
protozoan parasites and the roles of NLRs and inflammasomes against these parasites.
G. duodenalis, E. histolytica, T. vaginalis, Plasmodium parasite, T. cruzi, Schistosomes
parasite, T. gondii, and Leishmania spp. activate the NLRP3 inflammasome. The
NLRP3 inflammasome protects the host in Giardia, T. cruzi, and E. histolytica infections. Also, its protective role in the case of Trichomonas infection has been suggested,
but more studies are needed. However, NLRP3 induces pathology during Schistosomes
and Malaria parasite infection. In T. gondii infection, NLRP3 causes inflammation and
limits the parasite load burden and propagation. This provides a new dimension in the
research on the role and exact mechanism of NLRP3 during T. gondii infection. The
NLRP3 inflammasome protects the host by clearing the parasitic load; NLRP3 provides
resistance toward some Leishmania spp. It alleviates the host's parasitic burden of L.
amazonensis and L. major. However, L. major or L. donovani induces chronic nonhealing infection-promoting lesion development. These contrary reports warrant more
research on Leishmaniasis. For developing new treatment strategies, studying the role
of NLRP3 in the host defense and inflammatory pathology is crucial in parasitic
protozoan infection.
The NLRP3 Inflammasome as a Target for Antiinflammatory Drugs
Page: 119-158 (40)
Author: Adekunle Babajide Rowaiye*, Oni Solomon Oluwasunmibare, Umar Suleiman Abubakar, Priscilla Aondona, Lorretha Chinonye Emenyeonu and Tarimoboere Agbalalah
DOI: 10.2174/9789815223941124010009
PDF Price: $15
Abstract
The Nod-like receptor protein 3 (NLRP3) inflammasome plays a vital role in
the nonspecific immune response to inflammatory triggers such as cellular infections,
injury, or stressors, and it has also been associated with several inflammation-related
diseases. NLRP3 inflammasome activation results in the production of
proinflammatory cytokines, contributing to an increased risk of inflammatory
conditions, such as cardiovascular, metabolic, infectious, and neurodegenerative
diseases. Several signaling pathways and cellular events involved in the NLRP3
inflammasome assembly and activation have been studied, and inhibitory mechanisms
have been identified. NLRP3 inflammasome inhibition decreases inflammation and
inflammasome-mediated cell death. In prospecting for novel anti-inflammatory
therapeutics, signaling molecules upstream or downstream on the NLRP3
inflammasome pathway can serve as viable drug targets. Effective inhibition of these
molecules culminates in the downregulation of the expression of proinflammatory
cytokines like interleukin-1beta (IL-1β) and IL-18. This chapter elucidates the various classes of NLRP3 inflammasome inhibitors, their resultant anti-inflammatory effects,
and various mechanisms of action.
The Potential Value of Sputum Level Interleukin38 and NLRP3 Inflammasome in Severe Childhood Asthma
Page: 159-181 (23)
Author: Agnès Hamzaoui*, Sabrine Louhaichi and Kamel Hamzaoui
DOI: 10.2174/9789815223941124010010
PDF Price: $15
Abstract
Asthma in children is associated with serious exacerbations that are
modulated by inflammation. The expression of inflammatory cytokines varies
according to the severity of the disease. The transition from the state of exacerbation of
the disease to the state of cure always passes through a relationship between
inflammatory and anti-inflammatory mediators. This study looks at the expression of
IL-38 and NLRP3 inflammasome in severe childhood asthma. NLRP3 inflammasome
is upregulated in severe asthma, contrasting with low levels of IL-38. The
inflammatory pattern of severe asthma in children is characterized by the expression of
IL-17, IL-32, IL-1β, and NLRP3 inflammasome.
Inflammasomes, Inflammation and Neuropathic Pain
Page: 182-215 (34)
Author: Lokesh Sharan, Anubrato Pal, Priya Saha and Ashutosh Kumar*
DOI: 10.2174/9789815223941124010011
PDF Price: $15
Abstract
Inflammasomes such as NOD-like receptor protein 1 (NLRP1), NLRP3,
NLR family CARD domain-containing protein 4 (NLRC4) and absent in melanoma 2
(AIM2) are the primary mediators of inflammation and its associated neuropathic pain.
These inflammasomes are activated leading to various autoimmune & metabolic
disorders, cancer, and other inflammatory diseases. The activation of inflammasomes
occurs due to molecular alterations like mitochondrial dysfunction, neuroinflammation,
lysosomal damage, oxidative stress, sensitization, and disinhibition, which lead to
proinflammatory pathways causing inflammasome-related neuropathic pain. Among
these inflammasomes, NLRP3 has been widely studied and proven to be the key player
in the development of neuropathy. In this chapter, we have summarized the role of
inflammasome and how NLRP3 is involved in neuropathic pain. Therefore, based on
the facts available, it has been suggested that focusing on inflammasome activity may
be a cutting-edge and successful treatment approach for neuropathic pain.
Introduction
Inflammation triggers specific metabolic pathways and if not resolved, translates into several painful diseases such as rheumatoid arthritis, lupus, Alzheimer's disease, cardiovascular disorders and psoriasis. Various processes have been explored to understand the factors behind inflammation and consequently, many mechanisms have been examined to suppress it. The nucleotide-binding domain like receptor 3 (NLRP3) inflammasome is an example of such factors which is responsible for triggering sterile and microbe induced inflammation. Studies of genetic variants of the related gene have revealed insights into the mRNA expression pathways that may help researchers to identify crucial disease mechanisms. This book is a review of the scientific findings of distinguished scholars who have studied NLRP3 inflammasome activation and its contribution in worsening the outcomes of inflammatory disorders. This collection of chapters covers many aspects of the multifaceted role of NLRP3 inflammasome. Beginning with airway inflammation and fibrosis, it progresses to explore its involvement in pulmonary hypertension, heart diseases, tuberculosis, cardiovascular complications, and childhood asthma. Additionally, it examines the inflammasome's impact on protozoan parasitic infections and neuropathic pain. The chapters not only elucidate the intricate mechanisms of NLRP3 activation but also discuss potential inhibitors and therapeutic targets. Readers will gain a comprehensive understanding of the NLRP3 inflammasome's diverse implications across different physiological contexts. The book includes references making this book a valuable treatise of insights for researchers, clinicians, and healthcare professionals.