title: Quantitative proteomics reveals the induction of mitophagy in tumor necrosis factor-α-activated (TNFα) macrophages.
abstract: Macrophages play an important role in innate and adaptive immunity as professional phagocytes capable of internalizing and degrading pathogens to derive antigens for presentation to T cells. They also produce pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that mediate local and systemic responses and direct the development of adaptive immunity. The present work describes the use of label-free quantitative proteomics to profile the dynamic changes of proteins from resting and TNF-α-activated mouse macrophages. These analyses revealed that TNF-α activation of macrophages led to the down-regulation of mitochondrial proteins and the differential regulation of several proteins involved in vesicle trafficking and immune response. Importantly, we found that the down-regulation of mitochondria proteins occurred through mitophagy and was specific to TNF-α, as other cytokines such as IL-1β and IFN-γ had no effect on mitochondria degradation. Furthermore, using a novel antigen presentation system, we observed that the induction of mitophagy by TNF-α enabled the processing and presentation of mitochondrial antigens at the cell surface by MHC class I molecules. These findings highlight an unsuspected role of TNF-α in mitophagy and expanded our understanding of the mechanisms responsible for MHC presentation of self-antigens.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Station Centre-ville, Montréal, Québec, Canada H3C 3J7.
authors.forename: Christina
authors.initials: C
authors.lastname: Bell
authors.forename: Luc
authors.initials: L
authors.lastname: English
authors.forename: Jonathan
authors.initials: J
authors.lastname: Boulais
authors.forename: Magali
authors.initials: M
authors.lastname: Chemali
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron-Lizotte
authors.forename: Michel
authors.initials: M
authors.lastname: Desjardins
authors.forename: Pierre
authors.initials: P
authors.lastname: Thibault
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000941:Antigens / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D019295:Computational Biology; D015536:Down-Regulation / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects*; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D060066:Protein Interaction Maps / Q000187:drug effects; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000941:Antigens; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020543:Proteome; D014409:Tumor Necrosis Factor-alpha; D054510:Phospholipases A2, Cytosolic