The NLRP3 Inflammasome: An Attentive Arbiter of Inflammatory Response

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.

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.

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.

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 . 

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.

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 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.

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 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.