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

Area of Science:

• Immunology
• Pediatric Respiratory Medicine
• Molecular Biology

Background:

• Protracted bacterial bronchitis (PBB) in children presents with chronic wet cough and elevated airway IL-1β, often linked to nontypeable Haemophilus influenzae (NTHi).
• The precise mechanisms underlying IL-1β-driven inflammation in PBB remain unclear.
• This research investigates the potential role of the NLRP3 and AIM2 inflammasome pathways in PBB pathogenesis.

Purpose of the Study:

• To elucidate the involvement of NLRP3 and AIM2 inflammasomes in the IL-1β-mediated inflammation characteristic of PBB.
• To compare inflammasome activation and IL-1β production in immune cells from children with PBB and healthy controls upon NTHi stimulation.

Main Methods:

• Cultured lung macrophages (BAL), PBMCs, monocytes, and monocyte-derived macrophages from PBB patients and controls.
• Stimulated cells with live NTHi and assessed IL-1β, NLRC4 expression, and inflammasome complex formation (NLRP3, AIM2, cleaved caspase-1, cleaved IL-1β) using microscopy.
• Utilized caspase-1 and NLRP3 inhibitors (Z-YVAD-FMK, MCC950) to evaluate their effects on IL-1β secretion.

Main Results:

• NTHi stimulation significantly increased IL-1β expression and decreased NLRC4 expression in PBB PBMCs.
• IL-1β secretion induced by NTHi in PBMCs was inhibited by caspase-1 and NLRP3 inhibitors.
• Visualized NLRP3 and AIM2 inflammasome complexes colocalized with cleaved caspase-1 and IL-1β in PBB BAL macrophages and NTHi-stimulated PBMCs, monocytes, and derived macrophages.

Conclusions:

• Both NLRP3 and AIM2 inflammasomes are likely key drivers of the IL-1β-dominated inflammation observed in protracted bacterial bronchitis.
• These findings highlight specific molecular targets for potential therapeutic interventions in PBB.