Advertisement

Ephrins and Eph Receptor Signaling in Tissue Repair and Fibrosis

  • Brian Wu
  • Jason S. Rockel
  • David Lagares
  • Mohit Kapoor
Scleroderma (J Varga, Section Editor)
  • 58 Downloads
Part of the following topical collections:
  1. Topical Collection on Scleroderma

Abstract

Purpose of Review

Fibrosis is a pathological feature of many human diseases that affect multiple organs. The development of anti-fibrotic therapies has been a difficult endeavor due to the complexity of signaling pathways associated with fibrogenic processes, complicating the identification and modulation of specific targets. Evidence suggests that ephrin ligands and Eph receptors are crucial signaling molecules that contribute to physiological wound repair and the development of tissue fibrosis. Here, we discuss recent advances in the understanding of ephrin and Eph signaling in tissue repair and fibrosis.

Recent Findings

Ephrin-B2 is implicated in fibrosis of multiple organs. Intercepting its signaling may help counteract fibrosis.

Summary

Ephrins and Eph receptors are candidate mediators of fibrosis. Ephrin-B2, in particular, promotes fibrogenic processes in multiple organs. Thus, therapeutic strategies targeting Ephrin-B2 signaling could yield new ways to treat organ fibrosis.

Keywords

Ephrins Eph receptor Ephrin-B2 Fibrosis 

Notes

Acknowledgments

BW is the recipient of the Training Graduate PhD Salary Award from The Arthritis Society (Canada). DL is supported in part by the NIH grant R01 HL147059-01, Start-up Package by Massachusetts General Hospital, Scleroderma Foundation New Investigator Grant, Scleroderma Research Foundation Investigator-Initiated Research Grant, American Thoracic Society Foundation/Pulmonary Fibrosis Foundation Research Grant, and Sponsored Research Grants from Boehringer Ingelheim, Unity Biotechnology, and Indalo Therapeutics. MK is supported in part by the Canada Research Chairs Program, Canadian Institute of Health Research, The Natural Sciences and Engineering Research Council of Canada (NSERC), Canadian Foundation for Innovation, The Krembil Foundation, Stem Cell Network, The Toronto General and Western Hospital Foundation, and The Arthritis Program, University Health Network.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Ho YY, Lagares D, Tager AM, Kapoor M. Fibrosis—a lethal component of systemic sclerosis. Nat Rev Rheumatol. 2014;10:390–402.PubMedGoogle Scholar
  2. 2.
    Allanore Y, Simms R, Distler O, Trojanowska M, Pope J, Denton CP, et al. Systemic sclerosis. Nat Rev Dis Primers. 2015;1:15002.PubMedGoogle Scholar
  3. 3.
    Wells AU, Denton CP. Interstitial lung disease in connective tissue disease--mechanisms and management. Nat Rev Rheumatol. 2014;10(12):728–39.PubMedGoogle Scholar
  4. 4.
    DiPietro LA. Angiogenesis and wound repair: when enough is enough. J Leukoc Biol. 2016;100(5):979–84.PubMedGoogle Scholar
  5. 5.
    Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012;49(1):35–43.PubMedGoogle Scholar
  6. 6.
    Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6(265):265sr6.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325–38.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Lisabeth EM, Falivelli G, Pasquale EB. Eph receptor signaling and ephrins. Cold Spring Harb Perspect Biol. 2013;5(9).  https://doi.org/10.1101/cshperspect.a009159.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Dai D, Huang Q, Nussinov R, Ma B. Promiscuous and specific recognition among ephrins and Eph receptors. Biochim Biophys Acta. 2014;1844(10):1729–40.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD, et al. Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci. 2004;7(5):501–9.PubMedGoogle Scholar
  11. 11.
    Dravis C, Henkemeyer M. Ephrin-B reverse signaling controls septation events at the embryonic midline through separate tyrosine phosphorylation-independent signaling avenues. Dev Biol. 2011;355(1):138–51.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Bochenek ML, Dickinson S, Astin JW, Adams RH, Nobes CD. Ephrin-B2 regulates endothelial cell morphology and motility independently of Eph-receptor binding. J Cell Sci. 2010;123(Pt 8):1235–46.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Sawamiphak S, Seidel S, Essmann CL, Wilkinson GA, Pitulescu ME, Acker T, et al. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature. 2010;465(7297):487–91.PubMedGoogle Scholar
  14. 14.
    Nakayama A, Nakayama M, Turner CJ, Hoing S, Lepore JJ, Adams RH. Ephrin-B2 controls PDGFRbeta internalization and signaling. Genes Dev. 2013;27(23):2576–89.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Davy A, Aubin J, Soriano P. Ephrin-B1 forward and reverse signaling are required during mouse development. Genes Dev. 2004;18(5):572–83.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Chen K, Bai H, Liu Y, Hoyle DL, Shen W-F, Wu L-Q, et al. EphB4 forward-signaling regulates cardiac progenitor development in mouse ES cells. J Cell Biochem. 2015;116(3):467–75.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Lagares D, Ghassemi-Kakroodi P, Tremblay C, Santos A, Probst CK, Franklin A, et al. ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis. Nat Med. 2017;23(12):1405–15.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Hong JY, Shin MH, Chung KS, Kim EY, Jung JY, Kang YA, et al. EphA2 receptor signaling mediates inflammatory responses in lipopolysaccharide-induced lung injury. Tuberc Respir Dis. 2015;78(3):218–26.Google Scholar
  19. 19.
    Carpenter TC, Schroeder W, Stenmark KR, Schmidt EP. Eph-A2 promotes permeability and inflammatory responses to bleomycin-induced lung injury. Am J Respir Cell Mol Biol. 2012;46(1):40–7.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Kaplan N, Fatima A, Peng H, Bryar PJ, Lavker RM, Getsios S. EphA2/Ephrin-A1 signaling complexes restrict corneal epithelial cell migration. Invest Ophthalmol Vis Sci. 2012;53(2):936–45.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Cheng N, Brantley DM, Liu H, Lin Q, Enriquez M, Gale N, et al. Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis. Mol Cancer Res. 2002;1(1):2–11.PubMedGoogle Scholar
  22. 22.
    Daniel TO, Stein E, Cerretti DP, St John PL, Robert B, Abrahamson DR. ELK and LERK-2 in developing kidney and microvascular endothelial assembly. Kidney Int Suppl. 1996;57:S73–81.PubMedGoogle Scholar
  23. 23.
    Dobrzanski P, Hunter K, Jones-Bolin S, Chang H, Robinson C, Pritchard S, et al. Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer Res. 2004;64(3):910–9.PubMedGoogle Scholar
  24. 24.
    Wijeratne D, Rodger J, Stevenson A, Wallace H, Prele CM, Wood FM, et al. Ephrin-A2 affects wound healing and scarring in a murine model of excisional injury. Burns. 2018.  https://doi.org/10.1016/j.burns.2018.10.002.
  25. 25.
    Nunan R, Campbell J, Mori R, Pitulescu ME, Jiang WG, Harding KG, et al. Ephrin-Bs drive junctional downregulation and actin stress fiber disassembly to enable wound re-epithelialization. Cell Rep. 2015;13(7):1380–95.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Solanas G, Cortina C, Sevillano M, Batlle E. Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nat Cell Biol. 2011;13:1100–7.PubMedGoogle Scholar
  27. 27.
    Sohl M, Lanner F, Farnebo F. Sp1 mediate hypoxia induced ephrinB2 expression via a hypoxia-inducible factor independent mechanism. Biochem Biophys Res Commun. 2010;391(1):24–7.PubMedGoogle Scholar
  28. 28.
    Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature. 2010;465(7297):483–6.PubMedGoogle Scholar
  29. 29.
    Hafner C, Meyer S, Hagen I, Becker B, Roesch A, Landthaler M, et al. Ephrin-B reverse signaling induces expression of wound healing associated genes in IEC-6 intestinal epithelial cells. World J Gastroenterol. 2005;11(29):4511–8.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Groppa E, Brkic S, Uccelli A, Wirth G, Korpisalo-Pirinen P, Filippova M, et al. EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF. EMBO Rep. 2018;19(5):e45054.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Erber R, Eichelsbacher U, Powajbo V, Korn T, Djonov V, Lin J, et al. EphB4 controls blood vascular morphogenesis during postnatal angiogenesis. EMBO J. 2006;25(3):628–41.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Leem AY, Shin MH, Douglas IS, Song JH, Chung KS, Kim EY, et al. All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling. Biochem Biophys Res Commun. 2017;491(3):721–6.PubMedGoogle Scholar
  33. 33.
    Xiong Y, Li KX, Wei H, Jiao L, Yu SY, Zeng L. Eph/ephrin signalling serves a bidirectional role in lipopolysaccharide-induced intestinal injury. Mol Med Rep. 2018;18(2):2171–81.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Funk SD, Yurdagul A Jr, Albert P, Traylor JG Jr, Jin L, Chen J, et al. EphA2 activation promotes the endothelial cell inflammatory response: a potential role in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(3):686–95.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Ruscitti F, Ravanetti F, Essers J, Ridwan Y, Belenkov S, Vos W, et al. Longitudinal assessment of bleomycin-induced lung fibrosis by micro-CT correlates with histological evaluation in mice. Multidiscip Respir Med. 2017;12:8.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Limjunyawong N, Mitzner W, Horton MR. A mouse model of chronic idiopathic pulmonary fibrosis. Phys Rep. 2014;2(2):e00249-e.Google Scholar
  37. 37.
    Li H, Du S, Yang L, Chen Y, Huang W, Zhang R, et al. Rapid pulmonary fibrosis induced by acute lung injury via a lipopolysaccharide three-hit regimen. Innate Immun. 2009;15(3):143–54.PubMedGoogle Scholar
  38. 38.
    Cho HJ, Hwang YS, Mood K, Ji YJ, Lim J, Morrison DK, et al. EphrinB1 interacts with CNK1 and promotes cell migration through c-Jun N-terminal kinase (JNK) activation. J Biol Chem. 2014;289(26):18556–68.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Ventrella R, Kaplan N, Hoover P, Perez White BE, Lavker RM, Getsios S. EphA2 transmembrane domain is uniquely required for keratinocyte migration by regulating Ephrin-A1 levels. J Investig Dermatol. 2018;138(10):2133–43.PubMedGoogle Scholar
  40. 40.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21.PubMedGoogle Scholar
  41. 41.
    Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol. 1995;146(1):56–66.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Tonnesen MG, Feng X, Clark RA. Angiogenesis in wound healing. J Investig Dermatol Symp Proc. 2000;5(1):40–6.PubMedGoogle Scholar
  43. 43.
    Cheng N, Brantley DM, Chen J. The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev. 2002;13(1):75–85.PubMedGoogle Scholar
  44. 44.
    Nakayama M, Nakayama A, van Lessen M, Yamamoto H, Hoffmann S, Drexler HCA, et al. Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nat Cell Biol. 2013;15:249–60.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Santos SC, Miguel C, Domingues I, Calado A, Zhu Z, Wu Y, et al. VEGF and VEGFR-2 (KDR) internalization is required for endothelial recovery during wound healing. Exp Cell Res. 2007;313(8):1561–74.PubMedGoogle Scholar
  46. 46.
    Semela D, Das A, Langer D, Kang N, Leof E, Shah V. Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterology. 2008;135(2):671–9.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Luzina IG, Atamas SP, Wise R, Wigley FM, Choi J, Xiao HQ, et al. Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients. Arthritis Rheum. 2003;48(8):2262–74.PubMedGoogle Scholar
  48. 48.
    Umeda N, Ozaki H, Hayashi H, Oshima K. Expression of ephrinB2 and its receptors on fibroproliferative membranes in ocular angiogenic diseases. Am J Ophthalmol. 2004;138(2):270–9.PubMedGoogle Scholar
  49. 49.
    Avouac J, Clemessy M, Distler JH, Gasc JM, Ruiz B, Vacher-Lavenu MC, et al. Enhanced expression of ephrins and thrombospondins in the dermis of patients with early diffuse systemic sclerosis: potential contribution to perturbed angiogenesis and fibrosis. Rheumatology. 2011;50(8):1494–504.PubMedGoogle Scholar
  50. 50.
    •• Finney AC, Funk SD, Green JM, Yurdagul A Jr, Rana MA, Pistorius R, et al. EphA2 expression regulates inflammation and fibroproliferative remodeling in atherosclerosis. Circulation. 2017;136(6):566–82 This study provides evidence for the role of EphA2 in atherosclerosis. PubMedPubMedCentralGoogle Scholar
  51. 51.
    DuSablon A, Kent S, Coburn A, Virag J. EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice. Cardiovasc Diabetol. 2014;13:114.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Habiel DM, Espindola MS, Jones IC, Coelho AL, Stripp B, Hogaboam CM. CCR10+ epithelial cells from idiopathic pulmonary fibrosis lungs drive remodeling. JCI Insight. 2018;3(16):e122211.PubMedCentralGoogle Scholar
  53. 53.
    •• Su SA, Yang D, Wu Y, Xie Y, Zhu W, Cai Z, et al. EphrinB2 regulates cardiac fibrosis through modulating the interaction of Stat3 and TGF-beta/Smad3 signaling. Circ Res. 2017;121(6):617–27 This study describes the role of EphrinB2-signaling in cardiac fibrosis. PubMedGoogle Scholar
  54. 54.
    Kida Y, Ieronimakis N, Schrimpf C, Reyes M, Duffield JS. EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury. J Am Soc Nephrol. 2013;24(4):559–72.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Mimche PN, Brady LM, Bray CF, Lee CM, Thapa M, King TP, et al. The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice. Hepatology. 2015;62(3):900–14.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Swords RT, Greenberg PL, Wei AH, Durrant S, Advani AS, Hertzberg MS, et al. KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: results from a phase 1 study. Leuk Res. 2016;50:123–31.PubMedGoogle Scholar
  57. 57.
    Swords RT, Wei AH, Durrant S, Advani AS, Hertzberg MS, Lewis ID, et al. KB004, a novel non-fucosylated Humaneered® antibody, targeting EphA3, is active and well tolerated in a phase I/II study of advanced hematologic malignancies. Blood. 2014;124(21):3756.Google Scholar
  58. 58.
    A trial of KB004 in patients with glioblastoma. https://ClinicalTrials.gov/show/NCT03374943. Accessed Nov 2018.
  59. 59.
    Moreira RK. Hepatic stellate cells and liver fibrosis. Arch Pathol Lab Med. 2007;131(11):1728–34.PubMedGoogle Scholar
  60. 60.
    Das A, Shergill U, Thakur L, Sinha S, Urrutia R, Mukhopadhyay D, et al. Ephrin B2/EphB4 pathway in hepatic stellate cells stimulates Erk-dependent VEGF production and sinusoidal endothelial cell recruitment. Am J Physiol Gastrointest Liver Physiol. 2010;298(6):G908–15.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Brian Wu
    • 1
    • 2
  • Jason S. Rockel
    • 1
  • David Lagares
    • 3
    • 4
    • 5
  • Mohit Kapoor
    • 1
    • 2
    • 6
  1. 1.The Arthritis Program, Krembil Research InstituteUniversity Health NetworkTorontoCanada
  2. 2.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  3. 3.Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and ImmunologyMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  4. 4.Department of Medicine, Division of Pulmonary and Critical Care MedicineMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  5. 5.Fibrosis Research CenterMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  6. 6.Department of SurgeryUniversity of TorontoTorontoCanada

Personalised recommendations