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.
Highlights
Asthma represents a serious global health problem that affects 1%–18% of the population of all age groups
An in-depth understanding of the heterogeneity of severe asthma (SA) and the immunological mechanisms underlying its pathophysiology is critical for the identification of novel biomarkers and molecular pathways that can be targeted in novel treatment modalities
Active IL-1β binds to the extracellular domain of the IL-1 type 1 receptor (IL-1R) that recruits the second receptor chain, termed IL-1R accessory protein (IL-1RAcP) [98]. This leads to the activation of intracellular signaling molecules, such as the myeloid differentiation primary response 88 (MYD88), Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IL-1R-associated kinases (IRAK), which, in turn, activate the nuclear factor-κB (NF-κB) transcription factor, eliciting cytokine gene expression [99]
Summary
Asthma represents a serious global health problem that affects 1%–18% of the population of all age groups. Asthma is characterized by variable symptoms of wheezing, dyspnea, chest tightness, coughing, and reversible airflow obstruction, and is usually associated with airway hyperresponsiveness (AHR) to innocuous environmental allergens and chronic airway inflammation. Factors, such as allergen or irritant exposure, respiratory infections, exercise, climate changes, and stress, are responsible for the disparities and severity of asthma symptoms [1]. A small percentage of asthmatics exhibit severe disease exacerbations despite the fact that they are already under treatment with high doses of inhaled and/or systemic corticosteroids [2,3] These patients suffer from severe asthma (SA) that is poorly controlled and, in some cases, life-threatening [4,5]. We present recent findings pertinent to targeting NLRP3 functions as a novel therapeutic approach for the control of inflammatory responses in the airways
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