@article{53eacbd733cb4312bbfba1ed03ac14ab,
title = "Leishmania Lipophosphoglycan Triggers Caspase-11 and the Non-canonical Activation of the NLRP3 Inflammasome",
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",
author = "{de Carvalho}, {Renan V.H.} and Andrade, {Warrison A.} and Lima-Junior, {Djalma S.} and Marisa Dilucca and {de Oliveira}, {Caroline V.} and Kun Wang and Nogueira, {Paula M.} and Rugani, {Jeronimo N.} and Soares, {Rodrigo P.} and Beverley, {Stephen M.} and Feng Shao and Zamboni, {Dario S.}",
note = "Funding Information: We would like to thank Maira Nakamura for technical support. We are grateful to Richard Flavell (Yale) for providing the Casp1/11?/? mice and to Vishva Dixit (Genentech) for providing the Nlrp3?/? Casp11?/? and Casp1/11?/?/Casp11Tg mice and the anti-CASP1 p20 antibody. This work was supported by grants from PEW, Training in Tropical Diseases/World Health Organization (TDR/WHO), FAEPA, INCTV/CNPq, CNPq (grants 401577/2014-7 and 445881/2014-3), and CRID/FAPESP and FAPESP (grants 2013/08216-2 and 2014/04684-4). R.P.S. was supported by FAPEMIG (grants PPM-X 00102-16 and PPM-X 00102-16) and S.M.B. was supported by NIH grant R01 AI031078. R.V.H.C., W.A.A., and D.S.L.-J. were supported by fellowships from FAPESP. D.S.Z. and R.P.S. are Research Fellows from CNPq. Funding Information: We would like to thank Maira Nakamura for technical support. We are grateful to Richard Flavell (Yale) for providing the Casp1/11 –/– mice and to Vishva Dixit (Genentech) for providing the Nlrp3 –/– , Casp11 –/– , and Casp1/11 –/– /Casp11 Tg mice and the anti-CASP1 p20 antibody. This work was supported by grants from PEW , Training in Tropical Diseases / World Health Organization (TDR/WHO), FAEPA, INCTV / CNPq , CNPq (grants 401577/2014-7 and 445881/2014-3 ), and CRID/FAPESP and FAPESP (grants 2013/08216-2 and 2014/04684-4 ). R.P.S. was supported by FAPEMIG (grants PPM-X 00102-16 and PPM-X 00102-16 ) and S.M.B. was supported by NIH grant R01 AI031078 . R.V.H.C., W.A.A., and D.S.L.-J. were supported by fellowships from FAPESP . D.S.Z. and R.P.S. are Research Fellows from CNPq . Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2019",
month = jan,
day = "8",
doi = "10.1016/j.celrep.2018.12.047",
language = "English",
volume = "26",
pages = "429--437.e5",
journal = "Cell Reports",
issn = "2211-1247",
number = "2",
}