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GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3

Cellular & Molecular Immunology (2024)Cite this article

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Abstract

The NLRP3 inflammasome functions as an inflammatory driver, but its relationship with lipid metabolic changes in early sepsis remains unclear. Here, we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine (LPC) and was positively correlated with the severity of sepsis. GITR is a costimulatory molecule that is mainly expressed on T cells, but its function in macrophages is largely unknown. Our in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage pyroptosis. Furthermore, in vivo studies using either cecal ligation and puncture (CLP) or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality, while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1β deficiency attenuated sepsis severity/lethality. Mechanistically, GITR specifically enhanced inflammasome activation by regulating the posttranslational modification (PTM) of NLRP3. GITR competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation, leading to decreasing ubiquitination but increasing acetylation of NLRP3. Overall, these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury, suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases.

GITR exacerbates LPC-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3. According to the model, LPC levels increase during the early stage of sepsis, inducing GITR expression on macrophages. GITR not only competes with NLRP3 for binding to the E3 ligase MARCH7 but also recruits MARCH7 to induce the degradation of the deacetylase SIRT2, leading to decreasing ubiquitination but increasing acetylation of NLRP3 and therefore exacerbating LPC-induced NLRP3 inflammasome activation, macrophage pyroptosis and systemic inflammatory injury.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31970893, 32270976), the Natural Science Foundation of Guangdong Province (2022A1515012541), the Guangdong Natural Science Fund for Distinguished Young Scholars (2016A030306004), the Fundamental Research Funds for the Central Universities (2023kypt18; 2023ptpy67; 19ykzd39; 19ykpy43), the China Postdoctoral Science Foundation (2022M723661), the 111 Project (No. B12003, B13037) and the Open Project of the Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education (2020kfkt08).

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Authors and Affiliations

  1. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

    Siping Liang, Jinyu Zhou, Can Cao, Yiting Liu, Siqi Ming, Juanfeng Lao, Qin Peng, Jiahui Yang & Minhao Wu

  2. Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China

    Siping Liang, Jinyu Zhou, Can Cao, Yiting Liu, Siqi Ming, Juanfeng Lao, Qin Peng, Jiahui Yang & Minhao Wu

  3. Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China

    Xi Liu & Yuqi Shang

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Contributions

SL, JZ, CC, YL, SM, XL, YS, JL, QP and JY conducted the experiments. SL, JZ, and CC acquired the data. SL, YL, SM, and MW provided scientific expertise and reagents. SL and MW designed the studies, analyzed the data, and wrote the manuscript. All the authors read the final version of the manuscript and approved its submission.

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Correspondence to Minhao Wu.

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Liang, S., Zhou, J., Cao, C. et al. GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01170-w

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