Marrocco 2021 J Immunol

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Marrocco A, Frawley K, Pearce LL, Peterson J, O'Brien JP, Mullett SJ, Wendell SG, St Croix CM, Mischler SE, Ortiz LA (2021) Metabolic adaptation of macrophages as mechanism of defense against crystalline silica. J Immunol 207:1627-40.

» PMID: 34433619 Open Access

Marrocco Antonella, Frawley Krystin, Pearce Linda L, Peterson James, O'Brien James P, Mullett Steven J, Wendell Stacy G, St Croix Claudette M, Mischler Steven E, Ortiz Luis A (2021) J Immunol

Abstract: Silicosis is a lethal pneumoconiosis for which no therapy is available. Silicosis is a global threat, and more than 2.2 million people per year are exposed to silica in the United States. The initial response to silica is mediated by innate immunity. Phagocytosis of silica particles by macrophages is followed by recruitment of mitochondria to phagosomes, generation of mitochondrial reactive oxygen species, and cytokine (IL-1β, TNF-α, IFN-β) release. In contrast with LPS, the metabolic remodeling of silica-exposed macrophages is unclear. This study contrasts mitochondrial and metabolic alterations induced by LPS and silica on macrophages and correlates them with macrophage viability and cytokine production, which are central to the pathogenesis of silicosis. Using high-resolution respirometer and liquid chromatography-high-resolution mass spectrometry, we determined the effects of silica and LPS on mitochondrial respiration and determined changes in central carbon metabolism of murine macrophage cell lines RAW 264.7 and IC-21. We show that silica induces metabolic reprogramming of macrophages. Silica, as well as LPS, enhances glucose uptake and increases aerobic glycolysis in macrophages. In contrast with LPS, silica affects mitochondria respiration, reducing complex I and enhancing complex II activity, to sustain cell viability. These mitochondrial alterations are associated in silica, but not in LPS-exposed macrophages, with reductions of tricarboxylic acid cycle intermediates, including succinate, itaconate, glutamate, and glutamine. Furthermore, in contrast with LPS, these silica-induced metabolic adaptations do not correlate with IL-1β or TNF-α production, but with the suppressed release of IFN-β. Our data highlight the importance of complex II activity and tricarboxylic acid cycle remodeling to macrophage survival and cytokine-mediated inflammation in silicosis.

Copyright © 2021 by The American Association of Immunologists, Inc.

Bioblast editor: Plangger M


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Other 

Organism: Mouse  Tissue;cell: Macrophage-derived 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

2021-09, AmR