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Gasdermin D as a cellular switch to orientate immune responses via IL-33 or IL-1β

Cellular & Molecular Immunology volume 20, pages 8–10 (2023)Cite this article

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The role of Gsdmd has been well described in pyroptosis, which is a form of cell death associated with tissue damage. During canonical inflammasome-induced pyroptosis, Gsdmd is proteolytically cleaved by activated caspase-1 to generate an active fragment with membrane pore-forming abilities, which allows the release of IL-1β and IL-18 through unconventional protein secretion [4]. In contrast, Chen et al. observed that following stimulation with the allergen protease papain, the formation of a novel p40 or p35 N-terminal (NT) Gsdmd fragment in murine MLE-12 or human A549 epithelial cell lines, respectively, occurred [3]. The appearance of these neofragments was concomitant with the delocalization of IL-33 from the cell nucleus and its release into the supernatant without apparent cell death or caspase activation. This effect was reversible after the removal of papain from the medium. To differentiate this observation from the conventional inflammasome-dependent pyroptosis mediated by Gsdmd, Chen et al. compared the effect of inflammasome activation and papain stimulation in murine bone marrow-derived macrophages (BMDMs). While activation of the inflammasome with lipopolysaccharide (LPS) and ATP or nigericin led to the cleavage of caspase-1 and the generation of a conventional pyroptotic Gsdmd fragment (35-kDa) plus lactate dehydrogenase (LDH) and IL-1β release in these cells, stimulation with papain promoted the appearance of p40 NT-Gsdmd and the secretion of IL-33. The lack of caspase involvement in papain-induced IL-33 secretion was confirmed with casp-1/casp-11-deficient BMDMs and the use of the pan-caspase inhibitor Z-VAD-FMK. On the other hand, the protease activity of papain and other allergen proteases was indispensable for IL-33 secretion. However, proteases from Alternaria alternata failed to induce p40 NT-Gsdmd but induced IL-33 release in vitro, suggesting an alternative pathway for IL-33 secretion via this protease.

The essential role of SGs in this newly described mechanism of IL-33 secretion was determined by visualising the formation of G3BP1-positive SG puncta in response to papain stimulation, which permitted the nuclear-cytosol translocation of IL-33. SGs are dynamic compartments assembled in the cytoplasm for the transport of RNA, ribosomal subunits and various proteins following translational arrest in response to stress [5]. Although SG assembly induced by arsenite and papain resulted in the nucleocytoplasmic translocation of IL-33, papain stimulation exclusively triggered the secretion of IL-33 into the supernatant, suggesting that SG assembly was an independent prerequisite event in IL-33 secretion.

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Acknowledgements

This work was supported by a grant from the Agence Nationale de la Recherche, France (ANR-19-CE17-0021 (BASIN)). We thank Dr Srinivasa Reddy Bonam for help with the high-resolution figure.

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  1. These authors contributed equally: Camille Chauvin, Sruthi Vijaya Retnakumar.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 75006, Paris, France

    Camille Chauvin, Sruthi Vijaya Retnakumar & Jagadeesh Bayry

  2. Department of Biological Sciences & Engineering, Indian Institute of Technology Palakkad, Palakkad, 678623, India

    Jagadeesh Bayry

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  1. Camille Chauvin
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  2. Sruthi Vijaya Retnakumar
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CC, SVR and JB performed the literature search and analyses and drafted the manuscript.

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Correspondence to Jagadeesh Bayry.

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Chauvin, C., Retnakumar, S.V. & Bayry, J. Gasdermin D as a cellular switch to orientate immune responses via IL-33 or IL-1β. Cell Mol Immunol 20, 8–10 (2023). https://doi.org/10.1038/s41423-022-00950-6

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