Skip to content
2000
image of Discoidin Domain Receptor 1 in Colonic Epithelial Cells: A Paracrine Driver of Colonic Fibrosis

Abstract

Introduction

This study investigated the role and potential mechanisms of discoidin domain receptor 1 (DDR1) in colon fibrogenesis.

Methods

We employed the DSS-induced chronic colitis and fibrosis model to evaluate the therapeutic potential of DDR1 knockout on colonic fibrosis. experiments involved generating human normal colonic epithelial cells (HIEC line) with DDR1 overexpression by lentivirus transfection. Human colonic fibroblasts were exposed to conditioned medium (CM) from the stably transfected cells that had been treated with transforming growth factor-beta 1 (TGF-β1). The cells were collected for molecular and biochemical analyses.

Results

Our proteomics analysis of DDR1 indicated significant enrichment of proteins involved in the extracellular matrix and fibrosis. In DSS-treated DDR1-KO mice, attenuation of colonic fibrosis and reduced activation of colonic fibroblasts were observed, contrasting significantly with their counterparts in DSS-treated WT mice. Colonic fibroblasts exhibited a marked increase in α-smooth muscle actin and type I collagen expression when exposed to CM from HIEC cells with DDR1 overexpression. Finally, overexpression of DDR1 markedly elevated the levels of p-PI3K, p-Akt, p-mTOR, p62, and LC3B in HIEC cells, resulting in enhanced secretion of TGF-β1.

Discussion

DDR1 in HIEC cells attenuates autophagy primarily by activating the PI3K/AKT/ mTOR signaling axis and concurrently increasing the autophagic markers LC3B and p62, thereby inducing paracrine secretion of TGF-β1, which drives the activation and proliferation of colonic fibroblasts and elicits a robust profibrotic response.

Conclusion

Our study suggests that DDR1 may be a potential therapeutic target for colonic fibrosis.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cpb/10.2174/0113892010418561250917063533
2025-10-08
2025-11-03

  • From This Site

    /content/journals/cpb/10.2174/0113892010418561250917063533
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Manetti M. Rosa I. Messerini L. Ibba-Manneschi L. Telocytes are reduced during fibrotic remodelling of the colonic wall in ulcerative colitis. J. Cell. Mol. Med. 2015 19 1 62 73 10.1111/jcmm.12457 25283476
    [Google Scholar]
  2. Beamish E.L. Johnson J. Shih B. Killick R. Dondelinger F. McGoran C. Brewster-Craig C. Davies A. Bhowmick A. Rigby R.J. Delay in loop ileostomy reversal surgery does not impact upon post-operative clinical outcomes. Complications are associated with an increased loss of microflora in the defunctioned intestine. Gut Microbes 2023 15 1 2199659 10.1080/19490976.2023.2199659 37055940
    [Google Scholar]
  3. Rieder F. Zimmermann E.M. Remzi F.H. Sandborn W.J. Crohn’s disease complicated by strictures: A systematic review. Gut 2013 62 7 1072 1084 10.1136/gutjnl‑2012‑304353 23626373
    [Google Scholar]
  4. Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases. Gastroenterology 2017 152 2 340 350.e6 10.1053/j.gastro.2016.09.047 27720839
    [Google Scholar]
  5. D’Haens G. Rieder F. Feagan B.G. Higgins P.D.R. Panés J. Maaser C. Rogler G. Löwenberg M. van der Voort R. Pinzani M. Peyrin-Biroulet L. Danese S. Allocca M. De Hertogh G. Denton C. Distler J. McCarrier K. McGovern D. Radstake T. Serrano D. Stoker J. Challenges in the pathophysiology, diagnosis, and management of intestinal fibrosis in inflammatory bowel disease. Gastroenterology 2022 162 1 26 31 10.1053/j.gastro.2019.05.072 31254502
    [Google Scholar]
  6. Xie Y. Fontenot L. Chupina Estrada A. Nelson B. Wang J. Shih D.Q. Ho W. Mattai S.A. Rieder F. Jensen D.D. Bunnett N.W. Koon H.W. Elafin reverses intestinal fibrosis by inhibiting cathepsin S-mediated protease-activated receptor 2. Cell. Mol. Gastroenterol. Hepatol. 2022 14 4 841 876 10.1016/j.jcmgh.2022.06.011 35840034
    [Google Scholar]
  7. Buday A. Őrsy P. Godó M. Mózes M. Kökény G. Lacza Z. Koller Á. Ungvári Z. Gross M.L. Benyó Z. Hamar P. Elevated systemic TGF-β impairs aortic vasomotor function through activation of NADPH oxidase-driven superoxide production and leads to hypertension, myocardial remodeling, and increased plaque formation in apoE −/− mice. Am. J. Physiol. Heart Circ. Physiol. 2010 299 2 H386 H395 10.1152/ajpheart.01042.2009 20511416
    [Google Scholar]
  8. Li H. Cai E. Cheng H. Ye X. Ma R. Zhu H. Chang X. FGA controls VEGFA secretion to promote angiogenesis by activating the VEGFR2-FAK signalling pathway. Front. Endocrinol. 2022 13 791860 10.3389/fendo.2022.791860 35498401
    [Google Scholar]
  9. Wu A. Chen Y. Liu Y. Lai Y. Liu D. miR 199b 5p inhibits triple negative breast cancer cell proliferation, migration and invasion by targeting DDR1. Oncol. Lett. 2018 16 4 4889 4896 10.3892/ol.2018.9255 30250555
    [Google Scholar]
  10. Chen E.A. Lin Y.S. Using synthetic peptides and recombinant collagen to understand DDR–collagen interactions. Biochim. Biophys. Acta Mol. Cell Res. 2019 1866 11 118458 10.1016/j.bbamcr.2019.03.005 30880148
    [Google Scholar]
  11. Creeden J.F. Kipp Z.A. Xu M. Flight R.M. Moseley H.N.B. Martinez G.J. Lee W.H. Alganem K. Imami A.S. McMullen M.R. Roychowdhury S. Nawabi A.M. Hipp J.A. Softic S. Weinman S.A. McCullumsmith R. Nagy L.E. Hinds T.D. Hepatic kinome atlas: An in‐depth identification of kinase pathways in liver fibrosis of humans and rodents. Hepatology 2022 76 5 1376 1388 10.1002/hep.32467 35313030
    [Google Scholar]
  12. Roberts M.E. Magowan L. Hall I.P. Johnson S.R. Discoidin domain receptor 1 regulates bronchial epithelial repair and matrix metalloproteinase production. Eur. Respir. J. 2011 37 6 1482 1493 10.1183/09031936.00039710 20884741
    [Google Scholar]
  13. Flamant M. Placier S. Rodenas A. Curat C.A. Vogel W.F. Chatziantoniou C. Dussaule J.C. Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease. J. Am. Soc. Nephrol. 2006 17 12 3374 3381 10.1681/ASN.2006060677 17093065
    [Google Scholar]
  14. Li X. Li Q. Xiong B. Chen H. Wang X. Zhang D. Discoidin domain receptor 1(DDR1) promote intestinal barrier disruption in Ulcerative Colitis through tight junction proteins degradation and epithelium apoptosis. Pharmacol. Res. 2022 183 106368 10.1016/j.phrs.2022.106368 35905891
    [Google Scholar]
  15. Cooper H.S. Murthy S.N. Shah R.S. Sedergran D.J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab. Invest. 1993 69 2 238 249 8350599
    [Google Scholar]
  16. Cao Y. Cheng K. Yang M. Deng Z. Ma Y. Yan X. Zhang Y. Jia Z. Wang J. Tu K. Liang J. Zhang M. Orally administration of cerium oxide nanozyme for computed tomography imaging and anti-inflammatory/anti-fibrotic therapy of inflammatory bowel disease. J. Nanobiotechnology 2023 21 1 21 10.1186/s12951‑023‑01770‑0 36658555
    [Google Scholar]
  17. D’Alessio S. Ungaro F. Noviello D. Lovisa S. Peyrin-Biroulet L. Danese S. Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat. Rev. Gastroenterol. Hepatol. 2022 19 3 169 184 10.1038/s41575‑021‑00543‑0 34876680
    [Google Scholar]
  18. He S. Wang J. Huang Y. Kong F. Yang R. Zhan Y. Li Z. Ye C. Meng L. Ren Y. Zhou Y. Chen G. Shen Z. Sun S. Zheng S. Dong R. Intestinal fibrosis in aganglionic segment of Hirschsprung’s disease revealed by single‐cell RNA sequencing. Clin. Transl. Med. 2023 13 2 e1193 10.1002/ctm2.1193 36738110
    [Google Scholar]
  19. Wang H. Wen Y. Wang L. Wang J. Chen H. Chen J. Guan J. Xie S. Chen Q. Wang Y. Tao A. Du Y. Yan J. DDR1 activation in macrophage promotes IPF by regulating NLRP3 inflammasome and macrophage reaction. 2022 Int. Immunopharmacol 113 (PtA) 109294 10.1016/j.intimp.2022.109294 36257259
    [Google Scholar]
  20. Borza C.M. Bolas G. Bock F. Zhang X. Akabogu F.C. Zhang M.Z. de Caestecker M. Yang M. Yang H. Lee E. Gewin L. Fogo A.B. McDonald W.H. Zent R. Pozzi A. DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3. JCI Insight 2022 7 3 e150887 10.1172/jci.insight.150887 34941574
    [Google Scholar]
  21. Meng Y. Zhao T. Han T. Chen H. Zhang Z. Zhang D. DDR1-induced paracrine factors of hepatocytes promote HSC activation and fibrosis development. Curr. Mol. Pharmacol. 2023 17 1 e220223213911 10.2174/1874467216666230222124515 36809965
    [Google Scholar]
  22. Ben Arfi K. Schneider C. Bennasroune A. Bouland N. Wolak-Thierry A. Collin G. Le C.C. Toussaint K. Hachet C. Lehrter V. Dedieu S. Bouché O. Morjani H. Boulagnon-Rombi C. Appert-Collin A. Discoidin domain receptor 1 expression in colon cancer: Roles and prognosis impact. Cancers 2022 14 4 928 10.3390/cancers14040928 35205677
    [Google Scholar]
  23. Yang Q. Huang J-G. Ren J-X. Chen Y. Tian M-F. Zhou L. Wen J. Song X-S. Wu Y-L. Yang Q-H. Jiang P-R. Wang J-N. M2 macrophages mediate fibrotic scar formation in the early stages after cerebral ischemia in rats. Neural Regen. Res. 2023 18 10 2208 2218 10.4103/1673‑5374.368299 37056140
    [Google Scholar]
  24. Li F.Q. Chen W.B. Luo Z.W. Chen Y.S. Sun Y.Y. Su X.P. Sun J.M. Chen S.Y. Bone marrow mesenchymal stem cell-derived exosomal microRNAs target PI3K/Akt signaling pathway to promote the activation of fibroblasts. World J. Stem Cells 2023 15 4 248 267 10.4252/wjsc.v15.i4.248 37181002
    [Google Scholar]
  25. Hao X. Jin Y. Zhang Y. Li S. Cui J. He H. Guo L. Yang F. Liu H. Inhibition of oncogenic Src ameliorates silica-induced pulmonary fibrosis via PI3K/AKT pathway. Int. J. Mol. Sci. 2023 24 1 774 10.3390/ijms24010774 36614217
    [Google Scholar]
  26. Cosin-Roger J. Canet F. Macias-Ceja D.C. Gisbert-Ferrándiz L. Ortiz-Masiá D. Esplugues J.V. Alós R. Navarro F. Barrachina M.D. Calatayud S. Autophagy stimulation as a potential strategy against intestinal fibrosis. Cells 2019 8 9 1078 10.3390/cells8091078 31540207
    [Google Scholar]
  27. Mathur R. Alam M.M. Zhao X.F. Liao Y. Shen J. Morgan S. Huang T. Lee H. Lee E. Huang Y. Zhu X. Induction of autophagy in Cx3cr1+ mononuclear cells limits IL-23/IL-22 axis-mediated intestinal fibrosis. Mucosal Immunol. 2019 12 3 612 623 10.1038/s41385‑019‑0146‑4 30765845
    [Google Scholar]
  28. Reilly R. Mroz M.S. Dempsey E. Wynne K. Keely S.J. McKone E.F. Hiebel C. Behl C. Coppinger J.A. Targeting the PI3K/Akt/mTOR signalling pathway in cystic Fibrosis. Sci. Rep. 2017 7 1 7642 10.1038/s41598‑017‑06588‑z 28794469
    [Google Scholar]
  29. He J. Peng H. Wang M. Liu Y. Guo X. Wang B. Dai L. Cheng X. Meng Z. Yuan L. Cai F. Tang Y. Isoliquiritigenin inhibits TGF-β1-induced fibrogenesis through activating autophagy via PI3K/AKT/mTOR pathway in MRC-5 cells. Acta Biochim. Biophys. Sin. (Shanghai) 2020 52 8 810 820 10.1093/abbs/gmaa067 32638014
    [Google Scholar]
  30. Zhang H. Chen W. Zhu H. Tsai H. Discoidin domain receptors in tumor biology and immunology: Progression and challenge. Biomolecules 2025 15 6 832 10.3390/biom15060832 40563472
    [Google Scholar]
  31. Tao J. Zhang M. Wen Z. Wang B. Zhang L. Ou Y. Tang X. Yu X. Jiang Q. Inhibition of EP300 and DDR1 synergistically alleviates pulmonary fibrosis in vitro and in vivo. Biomed. Pharmacother. 2018 106 1727 1733 10.1016/j.biopha.2018.07.132 30119248
    [Google Scholar]
  32. Moll S. Yasui Y. Abed A. Murata T. Shimada H. Maeda A. Fukushima N. Kanamori M. Uhles S. Badi L. Cagarelli T. Formentini I. Drawnel F. Georges G. Bergauer T. Gasser R. Bonfil R.D. Fridman R. Richter H. Funk J. Moeller M.J. Chatziantoniou C. Prunotto M. Selective pharmacological inhibition of DDR1 prevents experimentally-induced glomerulonephritis in prevention and therapeutic regime. J. Transl. Med. 2018 16 1 148 10.1186/s12967‑018‑1524‑5 29859097
    [Google Scholar]
/content/journals/cpb/10.2174/0113892010418561250917063533
Loading
Discoidin Domain Receptor 1 in Colonic Epithelial Cells: A Paracrine Driver of Colonic Fibrosis
Bentham Science Publishers ; https://doi.org/10.2174/0113892010418561250917063533
/content/journals/cpb/10.2174/0113892010418561250917063533
/content/journals/cpb/10.2174/0113892010418561250917063533
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: conditioned medium ; colonic epithelial cells ; Inflammatory bowel disease ; colonic fibrosis ; colonic fibroblasts ; discoidin domain receptor 1

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test