Pathogenic effects of inhibition of mTORC1/STAT3 axis facilitates Staphylococcus aureus -induced pyroptosis in human mac
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RESEARCH
Pathogenic effects of inhibition of mTORC1/ STAT3 axis facilitates Staphylococcus aureus‑induced pyroptosis in human macrophages Ruiyuan Yao1†, Yuhao Chen1,2†, Huifang Hao1†, Zhixin Guo1, Xiaoou Cheng1, Yuze Ma1, Qiang Ji1, Xiaoru Yang1, Yanfeng Wang1, Xihe Li1,3* and Zhigang Wang1*
Abstract Background: Pyroptosis is a recently identified pathway of caspase-mediated cell death in response to microbes, lipopolysaccharide, or chemotherapy in certain types of cells. However, the mechanism of how pyroptosis is regulated is not well-established. Methods: Herein, the intracellular bacteria were detected by staining and laser confocal microscopy and TEM. Live/ dead cell imaging assay was used to examine macrophage death. Western blot and immunohistochemical staining were used to examine the protein changes. IFA was used to identify typical budding vesicles of pyroptosis and the STAT3 nuclear localization. SEM was used to observe the morphological characteristics of pyroptosis. ELISA was used to detect the level of inflammatory cytokines. Pyroptosis was filmed in macrophages by LSCM. Results: S. aureus was internalized by human macrophages. Intracellular S. aureus induced macrophage death. S. aureus invasion increased the expression of NLRP3, Caspase1 (Casp-1 p20) and the accumulation of GSDMD-NT, GSDMD-NT pore structures, and the release of IL-1β and IL-18 in macrophages. Macrophages pyroptosis induced by S. aureus can be abrogated by blockage of S. aureus phagocytosis. The pyroptosic effect by S. aureus infection was promoted by either rapamycin or Stattic, a specific inhibitor for mTORC1 or STAT3. Inhibition of mTORC1 or STAT3 induced pyroptosis. mTORC1 regulated the pyroptosic gene expression through governing the nuclear localization of STAT3. mTORC1/STAT3 axis may play a regulatory role in pyroptosis within macrophages. Conclusions: S. aureus infection induces human macrophage pyroptosis, inhibition of mTORC1/STAT3 axis facilitates S. aureus-induced pyroptosis. mTORC1 and STAT3 are associated with pyroptosis. Our findings demonstrate a regulatory function of the mTORC1/STAT3 axis in macrophage pyroptosis, constituting a novel mechanism by which pyroptosis is regulated in macrophages. Keywords: Pyroptosis, Staphylococcus aureus, mTORC1, STAT3
*Correspondence: [email protected]; [email protected] † Ruiyuan Yao, Yuhao Chen, Huifang Hao have contributed equally to this work 1 State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China Full list of author information is available at the end of the article
Background Pyroptosis is a lytic form of caspase-dependent cell death, which encompasses caspase-1, -4, -5, and -11. Caspase-1 is activated by various canonical inflammasomes, and caspase-4/5/11 recognizes cytosolic bacterial lipopolysaccharide directly, both of which trigger pyroptosis [1].
© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 In
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