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Deletion of Cyclic GMP-AMP Synthase Aggravates Concanavalin A-Induced Acute Hepatic Injury by Facilitating Leukocyte Chemotaxis

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Abstract

Growing evidence demonstrates that cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, is essential for activating innate immunity and regulating inflammatory response against cellular damage. However, its role in immune-mediated hepatitis remains unclear. Here by challenging the cGAS knockout (KO) and their littermate wide-type (WT) mice with intravenous ConA injection to induce acute immune-mediated liver injury, we found that lack of cGAS drastically aggravated liver damage post ConA treatment for 24 h, reflected by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and amplified hepatic necrosis. The number of apoptotic hepatocytes was also significantly increased in the KO mice. RNA-sequencing analysis revealed that leukocyte chemotaxis and migration-related genes were remarkably upregulated in the KO livers. Consistently, immunofluorescence assays illustrated that the infiltrating F4/80-positive macrophages, Ly6G-positive neutrophils, and CD3-positive T cells were all significantly increased in the KO liver sections. The hepatic expression of the pro-inflammatory genes was elevated as well. Supporting the in vivo findings, the knockdown of cGAS in cultured macrophages showed promoted migration potential and enhanced pro-inflammatory gene expression. These results collectively demonstrated that deletion of cGAS could aggravate ConA-induced acute liver injury, at least at the 24-h time point, and its mechanism might be related to facilitating leukocyte chemotaxis and promoting liver inflammatory response.

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DATA AVAILABILITY

The data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

MATERIALS AVAILABILITY

The data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This research was funded by the National Natural Science Foundation of China (32071157 and 31900142).

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  1. Jiaxin Liu and Shuang Ji equally contributed to this study.

Authors and Affiliations

  1. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Jiaxin Liu, Shuang Ji, Meina Guo & Lihong Chen

  2. School of Bioengineering, Dalian University of Technology, Dalian, 116024, China

    Zhaiyi Liu

  3. School of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China

    Guangrui Yang

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  1. Jiaxin Liu
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Contributions

Performing experiments: J.L., Z.L., and M.G.; writing—original draft preparation: S.J. and J.L.; writing—review and editing: G.Y. and L.C.; supervision: L.C.; funding acquisition: L.C. and S.J. All authors read and approved the final manuscript.

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Correspondence to Lihong Chen.

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All animal experiments were conducted in accordance with the guidelines approved by the Dalian Medical University Animal Care and Use Committee.

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Liu, J., Ji, S., Liu, Z. et al. Deletion of Cyclic GMP-AMP Synthase Aggravates Concanavalin A-Induced Acute Hepatic Injury by Facilitating Leukocyte Chemotaxis. Inflammation 46, 1118–1130 (2023). https://doi.org/10.1007/s10753-023-01798-2

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