Proteomic and functional analysis of differential role of NLRC4, ASC and caspase-1 in macrophages activation by cytosolic flagellin

• Grant number: 13/16010-5
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2013
• End date: October 31, 2015
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Karina Ramalho Bortoluci
• Grantee: Karina Ramalho Bortoluci
• Host Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The flagellin monomer, structural protein subunit of the bacterial flagellum, is recognized by the extracellular TLR5, but is taken into the cell cytosol by type III (SPI Salmonella T3SS-1) and type IV (Legionella T4SS) secretion systems, where it is able to activate the inflammasome Naip5/NLRC4. The inflammasome NAIP5/NLRC4 may also contain the adapter molecule ASC and induces peculiar effector responses depending on the complex formed. NLRC4/ASC inflammasome complex induce auto-proteolytic cleavage of caspase-1 and processing of pro-IL-1² and IL-18. In contrast, in the absence of ASC, NLRC4 inflammasome activate caspase-1, but did not induce its auto-proteolytic cleavage promoting rapid cell death by pyroptosis. Further, in recent years, our group has been studying new effector mechanisms induced by recognition of cytosolic flagellin and recent data suggest that cytosolic flagellin also induces effector mechanisms independent of caspase-1, such as activaction of lysosomal pathways with the consequent peculiar formo f inflammatory cell death and IL-1± secretion. In conclusion, the cytosolic flagellin can activate effector mechanisms by distinct pathways, and molecular regulation of these pathways is not yet elucidated. Therefore, this study proposes to assess the differential role of NLRC4, ASC and caspase-1 in IL-1± and proteomics related to inflammation and cell death in macrophages activated by cytosolic flagellin. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CASSADO, ALEXANDRA DOS ANJOS; D'IMPERIO LIMA, MARIA REGINA; BORTOLUCI, KARINA RAMALHO. Revisiting mouse peritoneal macrophages: heterogeneity, development, and function. FRONTIERS IN IMMUNOLOGY, v. 6, MAY 19 2015. (13/16010-5, 13/07140-2)

BUZZO, CARINA DE LIMA; MEDINA, TIAGO; BRANCO, LAURA M.; LAGE, SILVIA L.; DE SOUZA FERREIRA, LUIS CARLOS; AMARANTE-MENDES, GUSTAVO P.; HOTTIGER, MICHAEL O.; DE CARVALHO, DANIEL D.; BORTOLUCI, KARINA R.. Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage. SCIENTIFIC REPORTS, v. 7, FEB 2 2017. (15/18003-1, 13/16010-5)

LAGE, SILVIA LUCENA; LONGO, CARLA; BRANCO, LAURA MIGLIARI; DA COSTA, THAIS BOCCIA; BUZZO, CARINA DE LIMA; BORTOLUCI, KARINA RAMALHO. Emerging concepts about NAIP/NLIRC4 inflammasomes. FRONTIERS IN IMMUNOLOGY, v. 5, JUL 2 2014. (13/16010-5)