Inhibition of the Inflammasome Activity of NLRP3 Attenuates HDM-Induced Allergic Asthma

Abstract

Inhaled allergens promote inflammatory response, tissue damage, and airway hyperresponsiveness in the lungs, leading to allergic asthma. NLRP3, as an immune sensor of infections and cellular stress, is associated with the development and exacerbation of asthma. However, the mechanism by which NLRP3 affects asthma requires further investigation. Here, we showed that inhaled house dust mite (HDM) promotes NLRP3 inflammasome activation in the lungs and specifically induces the maturation of caspase-1 and IL-1β in alveolar macrophages (AMs). Using Nlrp3-mutant mice, we found that NLRP3 promotes the inflammatory response and pathogenesis in HDM-induced allergic asthma in an inflammasome-dependent manner. Treatment with RRx-001, an NLRP3 inhibitor, significantly reduced inflammatory cell infiltration and mucus secretion in the airway. Our results showed that NLRP3 in myeloid cells promoted the development and progression of allergic asthma in an inflammasome-dependent manner. Small molecules targeting the NLRP3 inflammasome may provide new treatment options for this disease.

Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma

“…Consistently, MCC950 treatment also inhibited CRE-induced Muc5ac expression, highlighting the significance of NLRP3 inflammasome activation in mucus production ( 37 , 44 , 45 ). This finding was further supported by a recent study showring that inhibition of the NLRP3 inflammasome with MCC950 attenuated HDM-induced allergic inflammation and mucus production ( 74 ). Furthermore, treatment with IL-1β led to a dose-dependent response for Muc5ac expression, and blockade of IL-1β with neutralizing antibody significantly prevented Muc5ac expression in HBECs.…”

“…While NLRP3 inflammasome has been initially recognized to provide protective immunity by facilitating the clearance of pathogens in the airways, over-activation of NLRP3 inflammasome can lead to the exacerbation of airway inflammation and asthma ( 43 , 73 ). Of interest, NLRP3 inflammasome activation has been linked with Muc5ac overproduction ( 37 , 44 , 45 , 74 ) and allergic airway inflammation ( 42 , 46 – 49 , 74 ). These findings raise the possibility that allergen-induced NLRP3 inflammasome activation mediates the AhR signaling pathway-regulated airway inflammation and Muc5ac expression.…”

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“…Consistently, MCC950 treatment also inhibited CRE-induced Muc5ac expression, highlighting the significance of NLRP3 inflammasome activation in mucus production (37,44,45). This finding was further supported by a recent study showring that inhibition of the NLRP3 inflammasome with MCC950 attenuated HDM-induced allergic inflammation and mucus production (74). Furthermore, treatment with IL-1b led to a dose-dependent response for Muc5ac expression, and blockade of IL-1b with neutralizing antibody significantly prevented Muc5ac expression in HBECs.…”

“…While NLRP3 inflammasome has been initially recognized to provide protective immunity by facilitating the clearance of pathogens in the airways, over-activation of NLRP3 inflammasome can lead to the exacerbation of airway inflammation and asthma (43,73). Of interest, NLRP3 inflammasome activation has been linked with Muc5ac overproduction (37,44,45,74) and allergic airway inflammation (42,(46)(47)(48)(49)74). These findings raise the possibility that allergen-induced NLRP3 inflammasome activation mediates the AhR signaling pathway-regulated airway inflammation and Muc5ac expression.…”

Inborn Errors of Immunity Associated With Type 2 Inflammation in the USIDNET Registry

“…In contrast to deficiencies in innate immunity, we also identified an association between eosinophilia and NLRP3-mediated autoinflammatory syndromes. The NLRP3 inflammasome has been implicated in human eosinophilic disorders, as well as eosinophil recruitment and Th2 cytokine production in a mouse model of asthma ( 56 , 57 ).…”