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Cell Rep. 2019 Jan 8;26(2):429-437.e5. doi: 10.1016/j.celrep.2018.12.047.

Leishmania Lipophosphoglycan Triggers Caspase-11 and the Non-canonical Activation of the NLRP3 Inflammasome.

Author information

1
Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
2
National Institute of Biological Sciences, Beijing, 102206, China.
3
Instituto René Rachou, Fundação Oswaldo Cruz - FIOCRUZ, Belo Horizonte, Brazil.
4
Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
5
Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address: dszamboni@fmrp.usp.br.

Abstract

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.

KEYWORDS:

LPG; Leishmania; Leishmaniasis; NLRP3; caspase-1; caspase-11; inflammasome; lipophosphoglycan; macrophage; non-canonical inflammasome

PMID:
30625325
DOI:
10.1016/j.celrep.2018.12.047
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