Ephrins and Eph Receptor Signaling in Tissue Repair and Fibrosis
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.
Ephrin-B2 is implicated in fibrosis of multiple organs. Intercepting its signaling may help counteract fibrosis.
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.
KeywordsEphrins Eph receptor Ephrin-B2 Fibrosis
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.
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
- 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
- 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.
- 36.Limjunyawong N, Mitzner W, Horton MR. A mouse model of chronic idiopathic pulmonary fibrosis. Phys Rep. 2014;2(2):e00249-e.Google Scholar
- 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.•• 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
- 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.A trial of KB004 in patients with glioblastoma. https://ClinicalTrials.gov/show/NCT03374943. Accessed Nov 2018.
- 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