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

iScience

Takanori Komada¹  Tadayoshi Karasawa²  Yoshiyuki Mori³  Masafumi Takahashi³  Ryo Kamata³  Erika Hishida³  Sachiko Watanabe³  Tadashi Kasahara³  Homare Ito³  Hiroaki Kimura³  Emi Aizawa³  Naoya Yamada³ 

[1] Corresponding author;Department of Dentistry, Oral and Maxillofacial Surgery, Jichi Medical University, Tochigi, Japan;Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan;

关键词: Immunology;    Cell Biology;    Functional Aspects of Cell Biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown