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.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
Ho YY, Lagares D, Tager AM, Kapoor M. Fibrosis—a lethal component of systemic sclerosis. Nat Rev Rheumatol. 2014;10:390–402.
Allanore Y, Simms R, Distler O, Trojanowska M, Pope J, Denton CP, et al. Systemic sclerosis. Nat Rev Dis Primers. 2015;1:15002.
Wells AU, Denton CP. Interstitial lung disease in connective tissue disease--mechanisms and management. Nat Rev Rheumatol. 2014;10(12):728–39.
DiPietro LA. Angiogenesis and wound repair: when enough is enough. J Leukoc Biol. 2016;100(5):979–84.
Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012;49(1):35–43.
Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6(265):265sr6.
Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325–38.
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.
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.
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.
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.
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.
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.
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.
Davy A, Aubin J, Soriano P. Ephrin-B1 forward and reverse signaling are required during mouse development. Genes Dev. 2004;18(5):572–83.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Limjunyawong N, Mitzner W, Horton MR. A mouse model of chronic idiopathic pulmonary fibrosis. Phys Rep. 2014;2(2):e00249-e.
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.
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.
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.
Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21.
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.
Tonnesen MG, Feng X, Clark RA. Angiogenesis in wound healing. J Investig Dermatol Symp Proc. 2000;5(1):40–6.
Cheng N, Brantley DM, Chen J. The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev. 2002;13(1):75–85.
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.
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.
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.
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.
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.
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.
•• 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.
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.
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.
•• 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.
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.
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.
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.
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.
A trial of KB004 in patients with glioblastoma. https://ClinicalTrials.gov/show/NCT03374943. Accessed Nov 2018.
Moreira RK. Hepatic stellate cells and liver fibrosis. Arch Pathol Lab Med. 2007;131(11):1728–34.
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.
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.
Author information
Authors and Affiliations
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Scleroderma
Rights and permissions
About this article
Cite this article
Wu, B., Rockel, J.S., Lagares, D. et al. Ephrins and Eph Receptor Signaling in Tissue Repair and Fibrosis. Curr Rheumatol Rep 21, 23 (2019). https://doi.org/10.1007/s11926-019-0825-x
Published:
DOI: https://doi.org/10.1007/s11926-019-0825-x