Air pollution PM2.5 uptake by macrophages induces NLRP3 inflammasome-dependent IL1ß release through pro-inflammatory cytokine secretion and mitochondrial Complex I superoxide anion production.
Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B620
Abstract ID: 4400
Presenting Author:
Lourdes Caceres , Postdoctoral Fellow at Univ. of Chicago, Univ. Hosp. Freiburg
Abstract:
Exposure to air pollution fine particulate matter (PM2.5) exacerbates cardiorespiratory diseases by inducing local inflammation through alveolar macrophage uptake, triggering a systemic response with unclear underlying mechanisms. We aim to unravel how PM2.5 phagocytosis leads to NLRP3 inflammasome activation and IL1ß release. Inflammasome priming and assembly was time and dose dependent in THP1-ASC-GFP cells, consistently across different PM2.5 samples. IL1ß release was only observed after stimulation with transition metal-rich Residual Oil Fly Ash (ROFA) particles. We confirmed this in primary human monocyte derived macrophages and murine BMDMs. IL1ß release by ROFA was dependent on the NLRP3 inflammasome, as shown by lack of IL1ß production in NLRP3-deficient BMDMs, and by NLRP3 inhibition with MCC950. While ROFA promoted an upregulation of pro-inflammatory gene expression and cytokines release, MCC950 reduced TNFα, IL6, and CCL2 production. Using electron tomography, ROFA particles were observed inside intracellular vesicles and mitochondria, showing signs of structural damage. We identified lysosomal rupture, K+ efflux, and impaired mitochondrial function as key mechanisms for ROFA-mediated IL1ß release. Moreover, specific inhibition of superoxide anion production from mitochondrial respiratory Complex I, but not III, blunted IL1ß release in ROFA-exposed BMDMs. In summary, PM2.5 induces priming and activation of NLRP3 inflammasome, leading to IL1ß release.
Air pollution PM2.5 uptake by macrophages induces NLRP3 inflammasome-dependent IL1ß release through pro-inflammatory cytokine secretion and mitochondrial Complex I superoxide anion production.
Category
Poster and Podium (Block Symposium)