GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1α Release under Caspase-1 Inhibition

Emi Aizawa; Tadayoshi Karasawa; Sachiko Watanabe; Takanori Komada; Hiroaki Kimura; Ryo Kamata; Homare Ito; Erika Hishida; Naoya Yamada; Tadashi Kasahara; Yoshiyuki Mori; Masafumi Takahashi

doi:10.1016/j.isci.2020.101070

GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1α Release under Caspase-1 Inhibition

iScience. 2020 May 22;23(5):101070. doi: 10.1016/j.isci.2020.101070. Epub 2020 Apr 18.

Authors

Affiliations

¹ Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Department of Dentistry, Oral and Maxillofacial Surgery, Jichi Medical University, Tochigi, Japan.
² Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: tdys.karasawa@jichi.ac.jp.
³ Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
⁴ Department of Dentistry, Oral and Maxillofacial Surgery, Jichi Medical University, Tochigi, Japan.
⁵ Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: masafumi2@jichi.ac.jp.

Abstract

Pyroptosis is a form of regulated cell death that is characterized by gasdermin processing and increased membrane permeability. Caspase-1 and caspase-11 have been considered to be essential for gasdermin D processing associated with inflammasome activation. In the present study, we found that NLRP3 inflammasome activation induces delayed necrotic cell death via ASC in caspase-1/11-deficient macrophages. Furthermore, ASC-mediated caspase-8 activation and subsequent gasdermin E processing are necessary for caspase-1-independent necrotic cell death. We define this necrotic cell death as incomplete pyroptosis because IL-1β release, a key feature of pyroptosis, is absent, whereas IL-1α release is induced. Notably, unprocessed pro-IL-1β forms a molecular complex to be retained inside pyroptotic cells. Moreover, incomplete pyroptosis accompanied by IL-1α release is observed under the pharmacological inhibition of caspase-1 with VX765. These findings suggest that caspase-1 inhibition during NLRP3 inflammasome activation modulates forms of cell death and permits the release of IL-1α from dying cells.

Keywords: Cell Biology; Functional Aspects of Cell Biology; Immunology.