GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1α Release under Caspase-1 Inhibition
GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1α Release under Caspase-1 Inhibition
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DOI：
10.1016/j.isci.2020.101070
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发表时间：
2020-05-22
期刊：
影响因子：
5.8
通讯作者：
Takahashi, Masafumi
中科院分区：
文献类型：
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作者：
Aizawa, Emi;Karasawa, Tadayoshi;Takahashi, Masafumi
焦亡是一种以gasdermin加工和膜通透性增加为特征的调节性细胞死亡形式。半胱天冬酶-1和半胱天冬酶-11被认为是与炎性小体激活相关的gasdermin D加工所必需的。在本研究中，我们发现NLRP 3炎性体激活通过ASC在caspase-1/11缺陷的巨噬细胞中诱导延迟性坏死细胞死亡。此外，ASC介导的caspase-8激活和随后的gasdermin E加工是caspase-1非依赖性坏死细胞死亡所必需的。我们将这种坏死性细胞死亡定义为不完全性焦亡，因为不存在IL-1 β释放（焦亡的关键特征），而IL-1 α释放被诱导。值得注意的是，未加工的pro-IL-1 β形成一种分子复合物，被保留在pyroptotic细胞内。此外，在用VX 765药理学抑制胱天蛋白酶-1的情况下观察到伴随IL-1 α释放的不完全的焦亡。这些发现表明，在NLRP 3炎性小体激活期间，半胱天冬酶-1抑制调节细胞死亡的形式，并允许从垂死细胞释放IL-1 α。
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-1 beta release, a key feature of pyroptosis, is absent, whereas IL-1 alpha release is induced. Notably, unprocessed pro-IL-1 beta forms amolecular complex to be retained inside pyroptotic cells. Moreover, incomplete pyroptosis accompanied by IL-1 alpha 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-1 alpha from dying cells.