Soluble Uric Acid Activates the NLRP3 Inflammasome

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Braga, Tarcio Teodoro ; Forni, Maria Fernanda ; Correa-Costa, Matheus ; Ramos, Rodrigo Nalio ; Barbuto, Jose Alexandre ; Branco, Paola ; Castoldi, Angela ; Hiyane, Meire Ioshie ; Davanso, Mariana Rodrigues ; Latz, Eicke ; Franklin, Bernardo S. ; Kowaltowski, Alicia J. ; Saraiva Camara, Niels Olsen

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 7, JAN 13 2017.
• Citações Web of Science: 51

Resumo

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-1 beta. 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-1 beta 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. (AU)

• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 12/02270-2 - Novos mecanismos celulares, moleculares e imunológicos das lesões renais agudas e crônicas: busca por novas estratégias terapêuticas
• Beneficiário: Niels Olsen Saraiva Câmara
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/06992-8 - Mecanismos celulares, moleculares e imunológicos gerados com a ativação de NLRP
• Beneficiário: Tárcio Teodoro Braga
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado