Targeting NLRP3 Inflammasome Activation in Severe Asthma

Abstract

Severe asthma (SA) is a chronic lung disease characterized by recurring symptoms of reversible airflow obstruction, airway hyper-responsiveness (AHR), and inflammation that is resistant to currently employed treatments. The nucleotide-binding oligomerization domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome is an intracellular sensor that detects microbial motifs and endogenous danger signals and represents a key component of innate immune responses in the airways. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18 as well as pyroptosis. Accumulating evidence proposes that NLRP3 activation is critically involved in asthma pathogenesis. In fact, although NLRP3 facilitates the clearance of pathogens in the airways, persistent NLRP3 activation by inhaled irritants and/or innocuous environmental allergens can lead to overt pulmonary inflammation and exacerbation of asthma manifestations. Notably, administration of NLRP3 inhibitors in asthma models restrains AHR and pulmonary inflammation. Here, we provide an overview of the pathophysiology of SA, present molecular mechanisms underlying aberrant inflammatory responses in the airways, summarize recent studies pertinent to the biology and functions of NLRP3, and discuss the role of NLRP3 in the pathogenesis of asthma. Finally, we contemplate the potential of targeting NLRP3 as a novel therapeutic approach for the management of SA.

The Inhibition of NLRP3 Inflammasome and IL-6 Production by Hibiscus noldeae Baker f. Derived Constituents Provides a Link to Its Anti-Inflammatory Therapeutic Potentials

“…An important body of studies have proven the associations between neutrophilic asthma and increased IL-1β responses induced by the excessive NLRP3 inflammasome activation. This raises the possibility of targeting different inflammasome components as substantial therapeutic targets in neutrophil-dominated forms of severe, steroid-refractory asthma [ 16 ]. The analysis of inflammasome formation is mostly investigated through the monitoring of downstream processes and outcomes, the presence of cleaved caspase-1 enzyme being the most widely used method, as well as the caspase-1 activity on substrates such as pro-IL-1β, pro-IL-18, and pro-gasdermin-D [ 14 ].…”

“…Several pieces of evidence from research suggest that inflammasomes and/or their components and effectors are associated with the physio-pathogenesis of asthma and other respiratory diseases including COPD, SARS CoV-2, etc. [ 15 , 16 , 17 , 18 ]. In fact, it has been reported that the excessive release of active IL-1β and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) specks leads to the induction of neutrophil-dominated inflammatory responses in the airways that contributes to the pathogenesis of COPD and neutrophilic asthma [ 16 , 17 ].…”

“…The neutrophilic asthma is the most severe and has been reported to be refractory to the corticoid-based treatment [ 16 ]. Despite this resistance, the use of corticosteroids remains the basic treatment for several respiratory diseases involving cytokine storms.…”

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

“…Inflammasomes contribute to the pathogenesis of chronic skin disorders such as psoriasis and acne [ 20 , 21 , 22 , 23 ]. They have also been linked to asthma and allergic inflammation [ 24 , 25 , 26 , 27 ]. And inflammasomes are mediators of certain acute inflammatory conditions, such as gout and the respiratory distress syndrome associated with the late stage of certain viral lung infections, including COVID-19 [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”

The Relationship Between Gene Expression Pattern and the Severity of Asthma

“…This may be related to the metabolism of asthma after drug treatment(Cahill, et al 2017; Peters and Busse 2017). In addition, some allergens interact with NOD like receptors on airway epithelial cells, and act as "danger signals" to induce asthma(Theofani, et al 2019).…”