Enhanced IL-1β Release Following NLRP3 and AIM2 Inflammasome Stimulation Is Linked to mtROS in Airway Macrophages in Pulmonary Fibrosis

Frontiers in Immunology

Eirini Vasarmidi¹  Nikolaos Tzanakis¹  Semeli Mastrodimou¹  Eliza Tsitoura¹  Katerina Antoniou¹  Eleni Bibaki¹  Rachele Invernizzi²  Athina Trachalaki³  Toby M. Maher³  Philip L. Molyneaux³ 

[1] Laboratory of Molecular and Cellular Pneumonology, Respiratory Medicine Department, School of Medicine, University of Crete, Heraklion, Greece;National Heart and Lung Institute, Imperial College London, London, United Kingdom;Royal Brompton Hospital, London, United Kingdom;

关键词: IPF – idiopathic pulmonary fibrosis;    ILD;    NLRP3;    AIM2;    NLRC4;    mtROS;   

DOI  :  10.3389/fimmu.2021.661811

来源: DOAJ

【 摘 要 】

Fibrotic Interstitial lung diseases (ILDs) are complex disorders of variable clinical behaviour. The majority of them cause significant morbidity, whilst Idiopathic Pulmonary Fibrosis (IPF) is recognised as the most relentless. NLRP3, AIM2, and NLRC4 inflammasomes are multiprotein complexes driving IL-1β release; a proinflammatory and profibrotic cytokine. Several pathogenetic factors associated with IPF are identified as inflammasome activators, including increases in mtROS and bacterial burden. Mitochondrial oxidation and alterations in bacterial burden in IPF and other ILDs may lead to augmented inflammasome activity in airway macrophages (AMs). IPF (n=14), non-IPF-ILDs (n=12) patients and healthy subjects (n=12) were prospectively recruited and AMs were isolated from bronchoalveolar lavage. IL-1β release resulting from NLRP3, AIM2 and NLRC4 inflammasomes stimulation in AMs were determined and baseline levels of mitochondrial ROS and microbial burden were also measured. Our results showed that NLRP3 was more inducible in IPF and other ILDs compared to controls. Additionally, following AIM2 activation IL-1β release was significantly higher in IPF compared to controls, whereas similar trends were observed in Non-IPF-ILDs. NLRC4 activation was similar across groups. mtROS was significantly associated with heightened NLRP3 and AIM2 activation, and mitochondrial antioxidant treatment limited inflammasome activation. Importantly, microbial burden was linked to baseline IL-1β release and AIM2 and IL-18 relative expression independently of mtROS. In conclusion, the above findings suggested a link between the overactivation of NLRP3 and AIM2 inflammasomes, driven by mitochondrial oxidation, in the pathogenesis of lung fibrosis while changes in the microbiota may prime the inflammasome in the lungs.

【 授权许可】

Unknown