title: Soluble Uric Acid Activates the NLRP3 Inflammasome.
abstract: Uric acid is a damage-associated molecular pattern (DAMP), released from ischemic tissues and dying cells which, when crystalized, is able to activate the NLRP3 inflammasome. Soluble uric acid (sUA) is found in high concentrations in the serum of great apes, and even higher in some diseases, before the appearance of crystals. In the present study, we sought to investigate whether uric acid, in the soluble form, could also activate the NLRP3 inflammasome and induce the production of IL-1β. We monitored ROS, mitochondrial area and respiratory parameters from macrophages following sUA stimulus. We observed that sUA is released in a hypoxic environment and is able to induce IL-1β release. This process is followed by production of mitochondrial ROS, ASC speck formation and caspase-1 activation. Nlrp3-/-macrophages presented a protected redox state, increased maximum and reserve oxygen consumption ratio (OCR) and higher VDAC protein levels when compared to WT and Myd88-/-cells. Using a disease model characterized by increased sUA levels, we observed a correlation between sUA, inflammasome activation and fibrosis. These findings suggest sUA activates the NLRP3 inflammasome. We propose that future therapeutic strategies for renal fibrosis should include strategies that block sUA or inhibit its recognition by phagocytes.
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.|Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Tarcio Teodoro
authors.initials: TT
authors.lastname: Braga
authors.affiliation: Departamento de Bioquímica, Instituto de Química, USP, São Paulo, Brazil.
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Forni
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Matheus
authors.initials: M
authors.lastname: Correa-Costa
authors.affiliation: Laboratory of Tumor Immunology Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Rodrigo Nalio
authors.initials: RN
authors.lastname: Ramos
authors.affiliation: Laboratory of Tumor Immunology Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Jose Alexandre
authors.initials: JA
authors.lastname: Barbuto
authors.affiliation: Department of Cellular Biology - Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Paola
authors.initials: P
authors.lastname: Branco
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Angela
authors.initials: A
authors.lastname: Castoldi
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Meire Ioshie
authors.initials: MI
authors.lastname: Hiyane
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Mariana Rodrigues
authors.initials: MR
authors.lastname: Davanso
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.|Division of Infectious Diseases &Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|German Center for Neurodegenerative Diseases, Bonn, Germany.|Center of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Bernardo S
authors.initials: BS
authors.lastname: Franklin
authors.affiliation: Departamento de Bioquímica, Instituto de Química, USP, São Paulo, Brazil.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.|Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.|Renal Pathophysiology Laboratory (LIM16), Faculty of Medicine, University of São Paulo, Brazil.
authors.forename: Niels Olsen Saraiva
authors.initials: NO
authors.lastname: Camara
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism*; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species; D050994:Voltage-Dependent Anion Channels; D014527:Uric Acid; D020170:Caspase 1