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Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis

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Abstract

Hypervirulent Klebsiella pneumoniae (hvKP) is a highly lethal opportunistic pathogen that elicits more severe inflammatory responses compared to classical Klebsiella pneumoniae (cKP). In this study, we investigated the interaction between hvKP infection and the anti-inflammatory immune response gene 1 (IRG1)-itaconate axis. Firstly, we demonstrated the activation of the IRG1-itaconate axis induced by hvKP, with a dependency on SYK signaling rather than STING. Importantly, we discovered that exogenous supplementation of itaconate effectively inhibited excessive inflammation by directly inhibiting SYK kinase at the 593 site through alkylation. Furthermore, our study revealed that itaconate effectively suppressed the classical activation phenotype (M1 phenotype) and macrophage cell death induced by hvKP. In vivo experiments demonstrated that itaconate administration mitigated hvKP-induced disturbances in intestinal immunopathology and homeostasis, including the restoration of intestinal barrier integrity and alleviation of dysbiosis in the gut microbiota, ultimately preventing fatal injury. Overall, our study expands the current understanding of the IRG1-itaconate axis in hvKP infection, providing a promising foundation for the development of innovative therapeutic strategies utilizing itaconate for the treatment of hvKP infections.

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Acknowledgements

We would like to dedicate this article in memory of the late Professor Jieshou Li, a renowned academician of the Chinese Academy of Engineering and a professor at Nanjing University. Professor Li was known for his exceptional kindness, amicability, and unwavering support towards students.

Funding

This work was supported by National Natural Science Foundation of China (82072223, 82072149, 82272237, 82272209), Key Research and Development Program of Jiangsu Province (BE2022823), the Natural Science Foundation of Jiangsu Province (BK20201116), Medical scientific research project of Jiangsu Health Committee (ZDB2020028, M2020052).

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  1. Yangguang Li and Yu Xu have contributed equally to this work.

Authors and Affiliations

  1. Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

    Yangguang Li, Yu Xu, Wenqi Wu, Jiaqi Kang, Peizhao Liu, Juanhan Liu, Xuanheng Li, Sicheng Li, Xiuwen Wu & Jianan Ren

  2. School of Medicine, Anhui University of Science and Technology, Huainan, 232000, China

    Weizhen Li

  3. School of Medicine, Southeast University, Nanjing, 210000, China

    Jiayang Li

  4. Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210009, China

    Yangguang Li, Haiyang Jiang, Chujun Ni, Lijuan Chen, Yun Zhao & Jianan Ren

  5. Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shanxi Province, China

    Wenbin Gong

  6. The Core Laboratory, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210009, China

    Mingda Liu

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  1. Yangguang Li
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Contributions

YL: Conceptualization, Methodology, Software, Investigation, Resources, Formal Analysis, Writing, Visualization. YX: Methodology, Software, Resources, Formal Analysis; WL: Conceptualization, Methodology, Resources, Investigation. JL: Methodology, Resources, Validation. WW, JK, HJ, PL, JL, WG, XL, CN, ML, LC and SL: Methodology, Investigation. XW, YZ and JR: Resources, Writing—Review & Editing, Supervision, Funding acquisition.

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Correspondence to Xiuwen Wu, Yun Zhao or Jianan Ren.

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The experimental protocols adhered to the Chinese guideline for the care and use of laboratory animals (Ministry of Science and Technology [2006] file no. 398) and received approval from the Institutional Animal Care and Use Committee of Jinling Hospital (approval number 2022DZGKJDWLS-0074).

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Li, Y., Xu, Y., Li, W. et al. Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis. Cell. Mol. Life Sci. 80, 337 (2023). https://doi.org/10.1007/s00018-023-04971-w

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