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Inflammasome-derived IL-1β production induces nitric oxide–mediated resistance to Leishmania

Nature Medicine volume 19, pages 909–915 (2013)Cite this article

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Abstract

Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. These parasites replicate intracellularly in macrophages, and the primary mechanisms underlying host resistance involve the production of nitric oxide (NO). In this study we show that the Nlrp3 inflammasome is activated in response to Leishmania infection and is important for the restriction of parasite replication both in macrophages and in vivo as demonstrated through the infection of inflammasome-deficient mice with Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum chagasi. Inflammasome-driven interleukin-1β (IL-1β) production facilitated host resistance to infection, as signaling through IL-1 receptor (IL-1R) and MyD88 was necessary and sufficient to trigger inducible nitric oxide synthase (NOS2)-mediated production of NO. In this manuscript we identify a major signaling platform for host resistance to Leishmania spp. infection and describe the molecular mechanisms underlying Leishmania-induced NO production.

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Figure 1: Caspase-1 is activated in response to L. amazonensis infection.
Figure 2: The Nlrp3 inflammasome is required for caspase-1 activation in macrophages infected with L. amazonensis.
Figure 3: L. amazonensis multiplication is increased in macrophages from inflammasome-deficient mice.
Figure 4: The Nlrp3 inflammasome is important for the in vivo restriction of L. amazonensis infection.
Figure 5: IL-1β and IFN-γ contribute to inflammasome-dependent parasite elimination through NO-dependent mechanisms.
Figure 6: IL-1R signaling is important for the control of L. amazonensis infection in macrophages and in vivo.

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Acknowledgements

We are grateful to M. Nakamura for technical assistance, F. Cunha (Universidade de São Paulo, Brazil) for providing IL-1Ra and V. Dixit (Genentech, USA) for providing us with the Nlrp3−/− mice and the antibody to caspase-1 p20. This work was supported by grants from Instituto Nacional de Ciência e Tecnologia de Vacinas (INCTV/CNPq), Núcleo de Apoio à Pesquisa em Doenças Inflamatórias (NAPDIN, grant 11.1.21625.01.0), Fundação de Amparo ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FAEPA), Special Programme for Research and Training in Tropical Diseases/World Health Organization (TDR/WHO, grant A60999 to D.S.Z.) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant 2006/52867-4 to D.S.Z.). D.L.C., V.C., L.D.C., A.L.N.S. and D.S.L.-J. (grant 2009/05054-6) are supported by fellowships from FAPESP. R.A.F. is an Investigator of the Howard Hughes Medical Institute. D.S.Z., M.B., M.T.B. and J.S.S. are Research Fellows from Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil.

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Author notes

  1. Tiago W P Mineo & Fredy R S Gutierrez

    Present address: Present addresses: Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, Brazil (T.W.P.M.), and School of Medicine, Antonio Nariño University, Bogotá, Colombia (F.R.S.G.).,

Authors and Affiliations

  1. Departmento de Biologia Celular, Molecular e Bioagentes Patogêncios, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.,

    Djalma S Lima-Junior, Larissa D Cunha, Alexandre L N Silva & Dario S Zamboni

  2. Departmento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.,

    Djalma S Lima-Junior, Diego L Costa, Vanessa Carregaro, Tiago W P Mineo, Fredy R S Gutierrez & João S Silva

  3. Departmento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Maria Bellio & Marcelo T Bozza

  4. Departmento de Ciências Biológicas e Centro de Terapia Celular e Molecular, Universidade Federal de São Paulo, São Paulo, Brazil

    Karina R Bortoluci

  5. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Richard A Flavell

  6. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA

    Richard A Flavell

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Contributions

D.S.L.-J. designed and performed experiments, analyzed data, generated figures and wrote the manuscript. D.L.C., V.C., L.D.C. and A.L.N.S. designed and performed experiments and analyzed data. T.W.P.M., F.R.S.G. and M.T.B. helped with data interpretation, discussed the hypotheses and participated in manuscript preparation. M.B., K.R.B., R.A.F. and J.S.S. provided reagents and discussed the hypotheses. D.S.Z. supervised the project, designed the experiments, helped with data interpretation, participated in data analysis and wrote the manuscript.

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Correspondence to Dario S Zamboni.

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Lima-Junior, D., Costa, D., Carregaro, V. et al. Inflammasome-derived IL-1β production induces nitric oxide–mediated resistance to Leishmania. Nat Med 19, 909–915 (2013). https://doi.org/10.1038/nm.3221

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