Role of inflammasome in severe, steroid-resistant asthma

Abstract

Purpose of review: Asthma is a common heterogeneous group of chronic inflammatory diseases with different pathological phenotypes classified based on the various clinical, physiological and immunobiological profiles of patients. Despite similar clinical symptoms, asthmatic patients may respond differently to treatment. Hence, asthma research is becoming more focused on deciphering the molecular and cellular pathways driving the different asthma endotypes. This review focuses on the role of inflammasome activation as one important mechanism reported in the pathogenesis of severe steroid resistant asthma (SSRA), a Th2-low asthma endotype. Although SSRA represents around 5-10% of asthmatic patients, it is responsible for the majority of asthma morbidity and more than 50% of asthma associated healthcare costs with clear unmet need. Therefore, deciphering the role of the inflammasome in SSRA pathogenesis, particularly in relation to neutrophil chemotaxis to the lungs, provides a novel target for therapy.

Recent findings: The literature highlighted several activators of inflammasomes that are elevated during SSRA and result in the release of proinflammatory mediators, mainly IL-1β and IL-18, through different signaling pathways. Consequently, the expression of NLRP3 and IL-1β is shown to be positively correlated with neutrophil recruitment and negatively correlated with airflow obstruction. Furthermore, exaggerated NLRP3 inflammasome/IL-1β activation is reported to be associated with glucocorticoid resistance.

Summary: In this review, we summarized the reported literature on the activators of the inflammasome during SSRA, the role of IL-1β and IL-18 in SSRA pathogenesis, and the pathways by which inflammasome activation contributes to steroid resistance. Finally, our review shed light on the different levels to target inflammasome involvement in an attempt to ameliorate the serious outcomes of SSRA.

Keywords: IL-18; IL-1β; Inflammasome; Neutrophilic asthma; Pyroptosis; Severe steroid resistant asthma (SSRA).

Fig. 1

Inflammasome activation and pyroptosis during SSRA. This figure summarizes the reported literature on signaling pathways leading to inflammasome activation during SSRA. These pathways involve IL-17, PI3Kδ, ROS production, eDNA, NETs and ROS. The activation of the inflammasome results in the release of chemokines and inflammatory mediators that attract more neutrophils and contribute to airway hyperresponsiveness. Several inhibitors such as MCC950 (CRID), ac-YAD-cho and anti-IL-1β act at different levels such as the NLRP3 inflammasome, caspase-1 and IL-1β respectively and were shown to reduce inflammation. PAMPs: pathogen associated molecular Patterns, DAMPs: damaged associated molecular patterns, ROS: reactive oxygen species, NETs: neutrophil extracellular traps, eDNA: extracellular DNA, DEX: dexamethasone.