Leishmania Lipophosphoglycan Triggers Caspase-11 and the Non-canonical Activation of the NLRP3 Inflammasome
Renan V.H. de Carvalho,
Warrison A. Andrade,
Djalma S. Lima-Junior,
Marisa Dilucca,
Caroline V. de Oliveira,
Kun Wang,
Paula M. Nogueira,
Jeronimo N. Rugani,
Rodrigo P. Soares,
Stephen M. Beverley,
Feng Shao,
Dario S. Zamboni
Affiliations
Renan V.H. de Carvalho
Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
Warrison A. Andrade
Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
Djalma S. Lima-Junior
Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
Marisa Dilucca
Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
Caroline V. de Oliveira
Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
Kun Wang
National Institute of Biological Sciences, Beijing, 102206, China
Paula M. Nogueira
Instituto René Rachou, Fundação Oswaldo Cruz - FIOCRUZ, Belo Horizonte, Brazil
Jeronimo N. Rugani
Instituto René Rachou, Fundação Oswaldo Cruz - FIOCRUZ, Belo Horizonte, Brazil
Rodrigo P. Soares
Instituto René Rachou, Fundação Oswaldo Cruz - FIOCRUZ, Belo Horizonte, Brazil
Stephen M. Beverley
Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Feng Shao
National Institute of Biological Sciences, Beijing, 102206, China
Dario S. Zamboni
Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil; Corresponding author
Summary: Activation of the NLRP3 inflammasome by Leishmania parasites is critical for the outcome of leishmaniasis, a disease that affects millions of people worldwide. We investigate the mechanisms involved in NLRP3 activation and demonstrate that caspase-11 (CASP11) is activated in response to infection by Leishmania species and triggers the non-canonical activation of NLRP3. This process accounts for host resistance to infection in macrophages and in vivo. We identify the parasite membrane glycoconjugate lipophosphoglycan (LPG) as the molecule involved in CASP11 activation. Cytosolic delivery of LPG in macrophages triggers CASP11 activation, and infections performed with Lpg1–/– parasites reduce CASP11/NLRP3 activation. Unlike bacterial LPS, purified LPG does not activate mouse CASP11 (or human Casp4) in vitro, suggesting the participation of additional molecules for LPG-mediated CASP11 activation. Our data identify a parasite molecule involved in CASP11 activation, thereby establishing the mechanisms underlying inflammasome activation in response to Leishmania species. : Activation of the NLRP3 inflammasome is critical for the outcome of leishmaniasis. De Carvalho et al. show that Leishmania lipophosphoglycan (LPG) triggers caspase-11 activation in macrophage cytoplasm and the non-canonical activation of NLRP3, thereby establishing the mechanisms underlying NLRP3 activation in response to Leishmania. Keywords: Leishmania, inflammasome, caspase-11, lipophosphoglycan, LPG, caspase-1, NLRP3, macrophage, non-canonical inflammasome, Leishmaniasis