Multiple inflammasomes may regulate the interleukin-1-driven inflammation in protracted bacterial bronchitis

Alice C-H Chen , Hai B. Tran, Yang Xi , Stephanie Yerkovich, Katherine J. Baines, Susan Pizzutto, Melanie Carroll, Avril A.B. Robertson, Matthew A. Cooper, Kate Schroder, Jodie L. Simpson, Peter G. Gibson, Greg Hodge, Ian B. Masters, Helen M. Buntain, Helen L. Petsky, Samantha J. Prime, Anne Chang, Sandra Hodge, John W. Upham

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    Abstract

    Protracted bacterial bronchitis (PBB) in young children is characterised by prolonged wet cough, prominent airway interleukin (IL)-1β expression and infection, often with nontypeable Haemophilus influenzae (NTHi). The mechanisms responsible for IL-1-driven inflammation in PBB are poorly understood. We hypothesised that the inflammation in PBB involves the NLRP3 and/or AIM2 inflammasome/IL-1β axis. Lung macrophages obtained from bronchoalveolar lavage (BAL), peripheral blood mononuclear cells (PBMCs), blood monocytes and monocyte-derived macrophages from patients with PBB and age-matched healthy controls were cultured in control medium or exposed to live NTHi. In healthy adult PBMCs, CD14+ monocytes contributed to 95% of total IL-1β-producing cells upon NTHi stimulation. Stimulation of PBB PBMCs with NTHi significantly increased IL-1β expression (p<0.001), but decreased NLRC4 expression (p<0.01). NTHi induced IL-1β secretion in PBMCs from both healthy controls and patients with recurrent PBB. This was inhibited by Z-YVAD-FMK (a caspase-1 selective inhibitor) and by MCC950 (a NLRP3 selective inhibitor). In PBB BAL macrophages inflammasome complexes were visualised as fluorescence specks of NLRP3 or AIM2 colocalised with cleaved caspase-1 and cleaved IL-1β. NTHi stimulation induced formation of specks of cleaved IL-1β, NLRP3 and AIM2 in PBMCs, blood monocytes and monocyte-derived macrophages. We conclude that both the NLRP3 and AIM2 inflammasomes probably drive the IL-1β-dominated inflammation in PBB.
    Original languageEnglish
    Pages (from-to)1-11
    Number of pages11
    JournalEuropean Respiratory Journal
    Volume4
    Issue number1
    DOIs
    Publication statusPublished - 2018

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    Chen , A. C-H., Tran, H. B., Xi , Y., Yerkovich, S., J. Baines, K., Pizzutto, S., Carroll, M., Robertson, A. A. B., Cooper, M. A., Schroder, K., Simpson, J. L., Gibson, P. G., Hodge, G., Masters, I. B., Buntain, H. M., Petsky, H. L., Prime, S. J., Chang, A., Hodge, S., & Upham, J. W. (2018). Multiple inflammasomes may regulate the interleukin-1-driven inflammation in protracted bacterial bronchitis. European Respiratory Journal, 4(1), 1-11. https://doi.org/10.1183/23120541.00130-2017