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

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 7, JAN 13 2017.
• Web of Science Citations: 41

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-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)

• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 14/06992-8 - Cellular, molecular and immunological mechanisms generated through NLRP activation
• Grantee: Tárcio Teodoro Braga
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 12/02270-2 - New cellular, molecular and immunological mechanisms involved in acute and chronic renal injury: the search for new therapeutical approaches
• Grantee: Niels Olsen Saraiva Câmara
• Support type: Research Projects - Thematic Grants