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Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease

Cellular & Molecular Immunology volume 21, pages 620–633 (2024)Cite this article

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Abstract

Peptidyl arginine deiminase 4 (PAD4) plays a pivotal role in infection and inflammatory diseases by facilitating the formation of neutrophil extracellular traps (NETs). However, the substrates of PAD4 and its exact role in inflammatory bowel disease (IBD) remain unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) and substrate citrullination mapping to decipher the role of PAD4 in intestinal inflammation associated with IBD. Our results demonstrated that PAD4 deficiency alleviated colonic inflammation and restored intestinal barrier function in a dextran sulfate sodium (DSS)-induced colitis mouse model. scRNA-seq analysis revealed significant alterations in intestinal cell populations, with reduced neutrophil numbers and changes in epithelial subsets upon PAD4 deletion. Gene expression analysis highlighted pathways related to inflammation and epithelial cell function. Furthermore, we found that neutrophil-derived extracellular vesicles (EVs) carrying PAD4 were secreted into intestinal epithelial cells (IECs). Within IECs, PAD4 citrullinates mitochondrial creatine kinase 1 (CKMT1) at the R242 site, leading to reduced CKMT1 protein stability via the autophagy pathway. This action compromises mitochondrial homeostasis, impairs intestinal barrier integrity, and induces IECs apoptosis. IEC-specific depletion of CKMT1 exacerbated intestinal inflammation and apoptosis in mice with colitis. Clinical analysis of IBD patients revealed elevated levels of PAD4, increased CKMT1 citrullination, and decreased CKMT1 expression. In summary, our findings highlight the crucial role of PAD4 in IBD, where it modulates IECs plasticity via CKMT1 citrullination, suggesting that PAD4 may be a potential therapeutic target for IBD.

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Data availability

Single-cell RNA-seq data have been deposited in the NCBI Sequence Read Archive (SRA) under the accession code PRJNA906274. The raw mass spectrometry data generated in this study have been submitted to the ProteomeXchange database (www.proteomexchange.org) under accession number PXD041504.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 82100587, No. 82170567), the National Key R&D Program of China (No. 2023YFC2413801, China), the Shanghai Sailing Program (No. 21YF1458700), the China National Postdoctoral Program for Innovative Talents (No. BX20220288), the China Postdoctoral Science Foundation (No. 2022M720138), the Program of Shanghai Academic Research Leader (No. 22XD1425000), the Deep Blue Project of Naval Medical University (Pilot Talent Plan), the Basic Medical Research Project of the First Affiliated Hospital of Naval Medical University (No. 2023PY06), the “Changying” Talent Program of Changhai Hospital of Naval Medical University, and the “Changjian” Talent Program of Changhai Hospital of Naval Medical University.

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  1. These authors contributed equally: Shuling Wang, Yihang Song, Zhijie Wang, Xin Chang, Haicong Wu, Ziwei Yan.

Authors and Affiliations

  1. National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Shuling Wang, Yihang Song, Zhijie Wang, Xin Chang, Haicong Wu, Tian Xia, Zhaoshen Li & Yu Bai

  2. National Key Laboratory of Immunology and Inflammation, Naval Medical University, Shanghai, 200433, China

    Shuling Wang, Yihang Song, Xin Chang, Haicong Wu, Ziwei Yan, Jiayi Wu, Wenjun Hu, Zhaoshen Li & Yu Bai

  3. Changhai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Shuling Wang, Zixuan He, Tian Xia, Zhaoshen Li & Yu Bai

  4. Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Shuling Wang, Yihang Song, Zhijie Wang, Ziwei Yan, Zixuan He, Le Kang, Wenjun Hu, Tian Xia, Zhaoshen Li & Yu Bai

  5. Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China

    Shuling Wang & Xingxing Ren

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  1. Shuling Wang
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Contributions

Shuling Wang, Yihang Song, Zhijie Wang, and Xin Chang designed the methodology and performed, analyzed, and interpreted the experiments. Haicong Wu and Ziwei Yan performed some of the animal experiments and data analysis. Jiayi Wu, Zixuan He, Le Kang, and Wenjun Hu supported some of the animal and cell experiments. Xingxing Ren, Zhaoshen Li, and Yu Bai were involved in developing the methodology, study conceptualization, and writing the original draft. All authors contributed to the review and editing of the manuscript. Zhaoshen Li and Yu Bai provided funding and supervised the execution of the study.

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Correspondence to Zhaoshen Li, Xingxing Ren or Yu Bai.

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Wang, S., Song, Y., Wang, Z. et al. Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease. Cell Mol Immunol 21, 620–633 (2024). https://doi.org/10.1038/s41423-024-01158-6

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