Characterization and inhibition of inflammasome responses in severe and non-severe asthma

Abstract

Background: Increased airway NLRP3 inflammasome-mediated IL-1β responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown. Objective: To investigate the activation and inhibition of inflammasome-mediated IL-1β responses in immune cells from patients with asthma. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1β release were assessed. Results: PBMCs from patients with non-severe or severe asthma produced more IL-1β in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1β in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1β release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1β release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1β release from PBMCs from all groups. Conclusion: An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease.