title: Inflammasome activation is reactive oxygen species dependent and mediates irinotecan-induced mucositis through IL-1β and IL-18 in mice.
abstract: Irinotecan is a useful chemotherapeutic for the treatment of various cancers. Irinotecan treatment is associated with mucositis, which clearly limits the use of the drug. Mechanisms that account for mucositis are only partially known. This study assessed mechanisms and the role of inflammasome activation in irinotecan-induced mucositis. Mucositis in mice was induced by irinotecan injection in C57BL/6 wild-type, gp91phox(-/-), il-18(-/-), casp-1(-/-), and asc(-/-) mice once a day for 4 consecutive days. In some experiments, mice received apocynin to inhibit NADPH oxidase (NOX), IL-1 receptor antagonist, or IL-18 binding protein to prevent activation of IL-1 and IL-18 receptors, respectively. Mice were euthanized 7 days after the beginning of irinotecan treatment, and small intestines were collected for analysis. Irinotecan treatment resulted in increased IL-1β and IL-18 production in ileum and NOX-2-dependent oxidative stress. gp91phox(-/-) and apocynin-treated mice had diminished oxidative stress and less severe mucositis. Furthermore, treatment with apocynin decreased caspase-1 activation and IL-1β and IL-18 production in the ileum. asc(-/-) and casp-1(-/-) mice also had less intestinal injury and decreased IL-1β and IL-18 production. Finally, both the absence of IL-18 and IL-1β resulted in reduced inflammatory response and attenuated intestinal injury. NOX-2-derived oxidative stress mediates inflammasome activation and inflammasome-dependent production of IL-1β and IL-18, which mediate tissue injury during irinotecan-induced mucositis in mice.
authors: Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Raquel D N
authors: RD
authors: Arifa
authors: Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Mila F M
authors: MF
authors: Madeira
authors: Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Talles P
authors: TP
authors: de Paula
authors: Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Renata L
authors: RL
authors: Lima
authors: Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Livia D
authors: LD
authors: Tavares
authors: Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Zélia
authors: Z
authors: Menezes-Garcia
authors: Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Caio T
authors: CT
authors: Fagundes
authors: Laboratory of Apoptosis, Department of Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Milene A
authors: MA
authors: Rachid
authors: INEM-UMR7355, Molecular Immunology, University and National Center for Scientific Research, Orleans, France.
authors: Bernhard
authors: B
authors: Ryffel
authors: Department of Cell and Molecular Biology, and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo (FMRP/USP), Ribeirão Preto, Brazil.
authors: Dario S
authors: DS
authors: Zamboni
authors: Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Mauro M
authors: MM
authors: Teixeira
authors: Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil. Electronic address: dani@icb.ufmg.br.
authors: Danielle G
authors: DG
authors: Souza
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives; D020170:Caspase 1 / Q000378:metabolism; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D000077146:Irinotecan; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052016:Mucositis / Q000139:chemically induced / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D000077146:Irinotecan; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020170:Caspase 1; D002166:Camptothecin