title: Endocytosis of indium-tin-oxide nanoparticles by macrophages provokes pyroptosis requiring NLRP3-ASC-Caspase1 axis that can be prevented by mesenchymal stem cells.
abstract: The biological effects of indium-tin-oxide (ITO) are of considerable importance because workers exposed to indium compounds have been diagnosed with interstitial lung disease or pulmonary alveolar proteinosis; however, the pathophysiology of these diseases is undefined. Here, mice intraperitoneally inoculated with ITO-nanoparticles (ITO-NPs) resulted in peritonitis dependent in NLRP3 inflammasome, with neutrophils recruitment and interleukin-1β (IL-1β) production. Withal peritoneal macrophages exposed ex vivo to ITO-NPs caused IL-1β secretion and cytolysis. Further, alveolar macrophages exposed to ITO-NPs in vitro showed ITO-NP endocytosis and production of tumor necrosis factor-α (TNF-α) and IL-1β, ensued cell death by cytolysis. This cell death was RIPK1-independent but caspase1-dependent, and thus identified as pyroptosis. Endocytosis of ITO-NPs by activated THP-1 cells induced pyroptosis with IL-1β/TNF-α production and cytolysis, but not in activated THP-1 cells with knockdown of NLRP3, ASC, or caspase1. However, exposing activated THP-1 cells with NLRP3 or ASC knockdown to ITO-NPs resulted in cell death but without cytolysis, with deficiency in IL-1β/TNF-α, and revealing features of apoptosis. While, mesenchymal stem cells (MSCs) co-cultured with macrophages impaired both inflammation and cell death induced by ITO-NPs. Together, our findings provide crucial insights to the pathophysiology of respiratory diseases caused by ITO particles, and identify MSCs as a potent therapeutic.
authors.affiliation: Center for Innovative and Translational Medicine (CITM), Kochi Medical School, Kochi University, Kochi, Japan.|Department of Environmental Medicine, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Naji
authors.affiliation: Department of Environmental Medicine, Kochi Medical School, Kochi University, Kochi, Japan.|Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Basilua André
authors.initials: BA
authors.lastname: Muzembo
authors.affiliation: Center for Innovative and Translational Medicine (CITM), Kochi Medical School, Kochi University, Kochi, Japan.|Science Research Center, Division of Biological Research, Life Sciences and Functional Materials, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yagyu
authors.affiliation: Center for Innovative and Translational Medicine (CITM), Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Baba
authors.affiliation: STROMALab, Université de Toulouse, UMR 5273 CNRS, INSERM U1031, EFS Pyrénées-Méditerranée, Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Deschaseaux
authors.affiliation: STROMALab, Université de Toulouse, UMR 5273 CNRS, INSERM U1031, EFS Pyrénées-Méditerranée, Toulouse, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Sensebé
authors.affiliation: Center for Innovative and Translational Medicine (CITM), Kochi Medical School, Kochi University, Kochi, Japan.|Department of Environmental Medicine, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Narufumi
authors.initials: N
authors.lastname: Suganuma
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004705:Endocytosis; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D010538:Peritonitis / Q000139:chemically induced; D000069292:Pyroptosis; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017971:Tin Compounds / Q000008:administration & dosage / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1; D053583:Interleukin-1beta; D011956:Receptors, Cell Surface; D017971:Tin Compounds; C498534:Pycard protein, mouse; C109984:indium tin oxide; C492716:Nlrp3 protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein