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Tubulointerstitial nephritis antigen-like 1 is a novel matricellular protein that promotes gastric bacterial colonization and gastritis in the setting of Helicobacter pylori infection

Cellular & Molecular Immunology volume 20, pages 924–940 (2023)Cite this article

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Abstract

The interaction between the gastric epithelium and immune cells plays key roles in H. pylori-associated pathology. Here, we demonstrate a procolonization and proinflammatory role of tubulointerstitial nephritis antigen-like 1 (TINAGL1), a newly discovered matricellular protein, in H. pylori infection. Increased TINAGL1 production by gastric epithelial cells (GECs) in the infected gastric mucosa was synergistically induced by H. pylori and IL-1β via the ERK-SP1 pathway in a cagA-dependent manner. Elevated human gastric TINAGL1 correlated with H. pylori colonization and the severity of gastritis, and mouse TINAGL1 derived from non-bone marrow-derived cells promoted bacterial colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Tinagl1−/− and Tinagl1ΔGEC mice and were increased in mice injected with mouse TINAGL1. Mechanistically, TINAGL1 suppressed CCL21 expression and promoted CCL2 production in GECs by directly binding to integrin α5β1 to inhibit ERK and activate the NF-κB pathway, respectively, which not only led to decreased gastric influx of moDCs via CCL21-CCR7-dependent migration and, as a direct consequence, reduced the bacterial clearance capacity of the H. pylori-specific Th1 response, thereby promoting H. pylori colonization, but also resulted in increased gastric influx of Ly6Chigh monocytes via CCL2-CCR2-dependent migration. In turn, TINAGL1 induced the production of the proinflammatory protein S100A11 by Ly6Chigh monocytes, promoting H. pylori-associated gastritis. In summary, we identified a model in which TINAGL1 collectively ensures H. pylori persistence and promotes gastritis.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82070578, 81870394, 82000530 and 81670510), Chongqing Natural Science Fund for Distinguished Young Scholars (cstc2019jcyjjqX0003), Science Innovation Capacity Promotion Project of Army Medical University (2019XQY03) and National Key Research and Development Program of China (2016YFC1302200) and Collaborative Innovation Center of Chinese Ministry of Education (2020–39).

Author contributions

All listed authors participated meaningfully in the study, and they have seen this manuscript and approved its submission. YZ designed the study. YZ and YST performed the research, analyzed the data, and wrote the draft of the article. WC, QMZ, RX and JYX revised the manuscript. YST, RX, JYX, PW, WYC, ZGS, ZBY, FYM, PC, LSP, JYZ and WQT performed the research and collected data. QMZ, RX, JYX, SMY and YLZ contributed reagents and human clinical samples.

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  1. These authors contributed equally: Yongsheng Teng, Rui Xie, Jingyu Xu.

Authors and Affiliations

  1. Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China

    Yongsheng Teng, Pan Wang, Wanyan Chen, Fangyuan Mao, Ping Cheng, Liusheng Peng, Jinyu Zhang & Quanming Zou

  2. The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, China

    Yongsheng Teng & Pan Wang

  3. The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou, China

    Rui Xie & Jingyu Xu

  4. Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China

    Zhiguo Shan, Zongbao Yan & Yongliang Zhao

  5. Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing, China

    Wenqing Tian

  6. Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China

    Shiming Yang

  7. La Trobe Institute of Molecular Science, La Trobe University, Bundoora, VIC, Australia

    Weisan Chen

  8. Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China

    Yuan Zhuang

  9. National Engineering Research Center of Immunological Products, Third Military Medical University, Chongqing, China

    Yuan Zhuang

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  1. Yongsheng Teng
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Teng, Y., Xie, R., Xu, J. et al. Tubulointerstitial nephritis antigen-like 1 is a novel matricellular protein that promotes gastric bacterial colonization and gastritis in the setting of Helicobacter pylori infection. Cell Mol Immunol 20, 924–940 (2023). https://doi.org/10.1038/s41423-023-01055-4

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