Gasdermin D and Gasdermin E Are Dispensable for Silica-Mediated IL-1β Secretion from Mouse Macrophages.

Q3 Medicine
Jennifer Leung, Michael Chang, Richard E Moore, Jargalsaikhan Dagvadorj, Fayyaz S Sutterwala, Suzanne L Cassel
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Abstract

Silica crystals activate the NLRP3 inflammasome in macrophages, resulting in the caspase-1-dependent secretion of the proinflammatory cytokine IL-1β. Caspase-1-mediated cleavage of gasdermin D (GSDMD) triggers the formation of GSDMD pores, which drive pyroptotic cell death and facilitate the rapid release of IL-1β. However, the role of GSDMD in silica-induced lung injury is unclear. In this study, we show that although silica-induced lung injury is dependent on the inflammasome adaptor ASC and IL-1R1 signaling, GSDMD is dispensable for acute lung injury. Although the early rapid secretion of IL-1β in response to ATP and nigericin was GSDMD dependent, GSDMD was not required for IL-1β release at later time points. Similarly, secretion of IL-1β from macrophages in response to silica and alum proceeded in a GSDMD-independent manner. We further found that gasdermin E did not contribute to macrophage IL-1β secretion in the absence of GSDMD in vitro and was also not necessary for silica-induced acute lung injury in vivo. These findings demonstrate that GSDMD and gasdermin E are dispensable for IL-1β secretion in response to silica in vitro and in silica-induced acute lung injury in vivo.

Gasdermin D和Gasdermin E对小鼠巨噬细胞由二氧化硅介导的IL-1β分泌起着不可或缺的作用。
二氧化硅晶体能激活巨噬细胞中的NLRP3炎性体,导致依赖于caspase-1的促炎细胞因子IL-1β的分泌。Caspase-1介导的gasdermin D(GSDMD)裂解会引发GSDMD孔的形成,从而推动细胞猝死并促进IL-1β的快速释放。然而,GSDMD 在二氧化硅诱导的肺损伤中的作用尚不清楚。本研究表明,虽然二氧化硅诱导的肺损伤依赖于炎性体适配体 ASC 和 IL-1R1 信号传导,但 GSDMD 对急性肺损伤是不可或缺的。虽然对 ATP 和尼格瑞辛反应的早期 IL-1β 的快速分泌依赖于 GSDMD,但后期 IL-1β 的释放并不需要 GSDMD。同样,巨噬细胞对二氧化硅和明矾的反应中 IL-1β 的分泌也不依赖于 GSDMD。我们进一步发现,在体外没有 GSDMD 的情况下,gasdermin E 不会促进巨噬细胞 IL-1β 的分泌,在体内二氧化硅诱导的急性肺损伤中也不需要 GSDMD。这些研究结果表明,GSDMD和gasdermin E对于体外二氧化硅反应和体内二氧化硅诱导的急性肺损伤中IL-1β的分泌是不可或缺的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
0
审稿时长
4 weeks
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