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Gasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection

Author

Listed:
  • Keyla S. G. de Sá

    (Universidade de São Paulo)

  • Luana A. Amaral

    (Universidade de São Paulo)

  • Tamara S. Rodrigues

    (Universidade de São Paulo)

  • Adriene Y. Ishimoto

    (Universidade de São Paulo)

  • Warrison A. C. Andrade

    (Universidade de São Paulo)

  • Leticia Almeida

    (Universidade de São Paulo)

  • Felipe Freitas-Castro

    (Universidade de São Paulo)

  • Sabrina S. Batah

    (Universidade de São Paulo)

  • Sergio C. Oliveira

    (Universidade Federal de Minas Gerais)

  • Mônica T. Pastorello

    (Universidade de São Paulo)

  • Alexandre T. Fabro

    (Universidade de São Paulo
    Universidade de São Paulo)

  • Dario S. Zamboni

    (Universidade de São Paulo)

Abstract

Intracellular parasites from the Leishmania genus cause Leishmaniasis, a disease affecting millions of people worldwide. NLRP3 inflammasome is key for disease outcome, but the molecular mechanisms upstream of the inflammasome activation are still unclear. Here, we demonstrate that despite the absence of pyroptosis, Gasdermin-D (GSDMD) is active at the early stages of Leishmania infection in macrophages, allowing transient cell permeabilization, potassium efflux, and NLRP3 inflammasome activation. Further, GSDMD is processed into a non-canonical 25 kDa fragment. Gsdmd–/– macrophages and mice exhibit less NLRP3 inflammasome activation and are highly susceptible to infection by several Leishmania species, confirming the role of GSDMD for inflammasome-mediated host resistance. Active NLRP3 inflammasome and GSDMD are present in skin biopsies of patients, demonstrating activation of this pathway in human leishmaniasis. Altogether, our findings reveal that Leishmania subverts the normal functions of GSDMD, an important molecule to promote inflammasome activation and immunity in Leishmaniasis.

Suggested Citation

  • Keyla S. G. de Sá & Luana A. Amaral & Tamara S. Rodrigues & Adriene Y. Ishimoto & Warrison A. C. Andrade & Leticia Almeida & Felipe Freitas-Castro & Sabrina S. Batah & Sergio C. Oliveira & Mônica T. P, 2023. "Gasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36626-6
    DOI: 10.1038/s41467-023-36626-6
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    References listed on IDEAS

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    1. Xing Liu & Zhibin Zhang & Jianbin Ruan & Youdong Pan & Venkat Giri Magupalli & Hao Wu & Judy Lieberman, 2016. "Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores," Nature, Nature, vol. 535(7610), pages 153-158, July.
    2. Jianjin Shi & Yue Zhao & Kun Wang & Xuyan Shi & Yue Wang & Huanwei Huang & Yinghua Zhuang & Tao Cai & Fengchao Wang & Feng Shao, 2015. "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death," Nature, Nature, vol. 526(7575), pages 660-665, October.
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