Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease

Abstract

Inflammasomes are specialized inflammatory signaling platforms that govern the maturation and secretion of proinflammatory cytokines, such as IL-1b and IL-18, through the regulation of caspase-1-dependent proteolytic processing. Several nucleotide binding domain leucine-rich repeat-containing receptor (NLR) family members (i.e., NLR family, pyrin domain containing [NLRP] 1, NLRP3, and NLR family, caspase recruitment domain containing-4 [NLRC4]) as well as the pyrin and hemopoietic expression, interferon-inducibility, nuclear localization domain-containing family member, absent in melanoma 2, can form inflammasome complexes in human cells. In particular, the NLRP3 inflammasome is activated in response to cellular stresses through a two-component pathway, involving Toll-like receptor 4-ligand interaction (priming) followed by a second signal, such as ATPdependent P2X purinoreceptor 7 receptor activation. Emerging studies suggest that the NLRP3 inflammasome can exert pleiotropic effects in human diseases with potentially both pro-and antipathogenic sequelae. Whereas NLRP3 inflammasome activation can serve as a vital component of host defense against invading bacteria and pathogens, excessive activation of the inflammasome can lead to inflammation-associated tissue injury in the setting of chronic disease. In addition, pyroptosis, an inflammasomeassociated mode of cell death, contributes to host defense. Recent research has described the regulation and function of the NLRP3 inflammasome in various pulmonary diseases, including acute lung injury and acute respiratory distress syndrome, sepsis, respiratory infections, chronic obstructive pulmonary disease, asthma, pulmonary hypertension, cystic fibrosis, and idiopathic pulmonary fibrosis. The NLRP3 and related inflammasomes, and their regulated cytokines or receptors, may represent novel diagnostic or therapeutic targets in pulmonary diseases and other diseases in which inflammation contributes to pathogenesis.

Ag-NP-induced interleukin-1beta upregulation in a lung co-culture model

“…Priming signal is typically triggered by ligand binding to toll-like receptors (TLRs) or NOD-like receptors (NLRs). This results in activation of NF-κB, which translocates to the nucleus and activates the transcription of NLRP3 and pro-IL-1β [2,20]. A second activation signal generated by a wide range of exogenous and endogenous stimuli including an ion flux, phagosomal destabilization, mitochondrial reactive oxygen species (mtROS), or mitochondrial DAMPs, which will result in NLRP-3 inflammasome assembly [19,[21][22].…”

“…So far, four inflammasomes have been identified, containing an inflammasome sensor, the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC-CARD), and pro-caspase-1. Inflammasome activation is crucial for host defense against pathogens but excessive or prolonged-activation, or loss of function, has been linked to autoinflammatory disorders, so a better understanding of toxicity associated with inflammasome activation is imperative for the prevention of autoimmune disorders, such as chronic asthma, inflammatory bowel disease (IBD), and many others [1][2][3][4][5].…”

“…Asthma is a chronic inflammatory disease characterized by airway inflammation, airway hyper-responsiveness and airway remodeling [2]. The inflammasome is activated by PAMPs and DAMPs, which are common exposure particulates known to intensify asthmatic symptoms.…”

“…IL-1β activation initiates downstream signaling pathways and stimulates pro-inflammatory processes in the airway, leading to airway constriction, pain, and labored breathing. IL-1β also has the ability to promote the production of other cytokines and chemokines at the site of inflammation, further exacerbating the pathology [2].…”

Current Concepts and Controversies in Innate Immunity of Cystic Fibrosis Lung Disease

“…TLR4), inducing NF-κB-dependent NLRP3 protein synthesis, followed by a second signal leading to full NLRP3 inflammasome assembly [77]. In CF airway epithelial cells, P. aeruginosa infection has been shown to trigger mitochondrial dysfunction and enhance mitochondrial Ca 2+ uptake, leading to NLRP3 inflammasome activation [78,79]. …”