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Autotaxin stimulates LPA2 receptor in macrophages and exacerbates dextran sulfate sodium-induced acute colitis

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Abstract

Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) and choline. ATX has been implicated in multiple chronic inflammatory diseases, but little is known about its role in the development of inflammatory bowel disease (IBD). Here, we investigated how ATX contributed to intestinal inflammation during colitis. We found that ATX expression levels were upregulated in the intestines of ulcerative colitis (UC) patients in acute state as well as in the intestines of dextran sulfate sodium (DSS)-induced colitis mice, which is likely due to increased infiltration of inflammatory cells including macrophages. Intriguingly, the inhibition of ATX activity led to reduced production of inflammatory cytokines, as well as attenuated colitis. These findings suggest that ATX may display strong pro-inflammatory properties. Supporting this, treatment with recombinant mouse ATX (rmATX) increased the production of inflammatory cytokines and enzymes in mouse macrophage cell line RAW264.7 and bone marrow-derived macrophages (BMDM), whereas silencing ATX by siRNA reduced LPS-stimulated production of pro-inflammatory factors. Notably, we found that the levels of LPA2 (an LPA receptor) were dramatically upregulated in rmATX-treated RAW264.7 cells and DSS-treated mice. Gene silencing of lpa2 in RAW264.7 cells by siRNA led to reduced production of inflammatory cytokines. Moreover, adenovirus-mediated delivery of lpa2 short hairpin RNA into DSS-treated mice ameliorated colitis. Collectively, our research suggests that ATX may exacerbate DSS-induced colitis by activating LPA2 receptor in macrophages and represent a promising target for the treatment of IBD.

Key messages

  • Increased ATX expression and secretion in colitic colons are likely due to increased infiltration of inflammatory cells including macrophages.

  • Recombinant ATX promotes, but ATX silencing inhibits, the production of inflammatory cytokines in LPS-stimulated RAW264.7 cells and BMDM.

  • •LPA2 mediates the pro-inflammatory effects of ATX on macrophages.

  • Inhibition of ATX and downregulation of LPA2 ameliorate DSS-induced colitis.

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Acknowledgments

We are obliged to the patients and healthy volunteers for their dedicated collaboration. This work was supported by National Natural Science Foundation of China, No. 81770528, 81974063 and Hubei Province Natural Science Foundation, No. 2018CKB902 to Yu Qin.

Funding

This work was supported by National Natural Science Foundation of China, No. 81770528, 81974063 and Hubei Province Natural Science Foundation, No. 2018CKB902 to Yu Qin.

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Author notes

  1. Zi Wang and Wenjie Shi contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology, Jiefang Avenue, 1095, 430030, Wuhan, People’s Republic of China

    Zi Wang, Wenjie Shi, Dean Tian, Hua Qin & Qin Yu

  2. Division of Gastroenterology, Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada

    Bruce A. Vallance, Hyungjun Yang & Hong B. Yu

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  1. Zi Wang
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Zi Wang, Wenjie Shi, Hua Qin, Hyungjun Yang, Hong B. Yu. Original draft preparation was performed by Zi Wang and Qin Yu, review and editing by Dean Tian, Bruce A. Vallance, and Hong B. Yu. Funding acquisition was obtained by Qin Yu. All authors read and approved the final manuscript.

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Correspondence to Hong B. Yu or Qin Yu.

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All animal experiments were performed in accordance with the relevant national guidelines. Written informed consent was obtained from all patients involved in this study. The use of samples in this study has been approved by the Institute Research Medical Ethics Committees of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.

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Wang, Z., Shi, W., Tian, D. et al. Autotaxin stimulates LPA2 receptor in macrophages and exacerbates dextran sulfate sodium-induced acute colitis. J Mol Med 98, 1781–1794 (2020). https://doi.org/10.1007/s00109-020-01997-6

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  • DOI: https://doi.org/10.1007/s00109-020-01997-6

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