Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis.
Adult
Aged
Animals
Bleomycin
/ toxicity
Cell Movement
Cell Proliferation
Collagen
Dipeptidyl Peptidase 4
/ genetics
Dipeptidyl-Peptidase IV Inhibitors
/ pharmacology
Disease Models, Animal
Female
Fibroblasts
/ metabolism
Fibrosis
Fluorescent Antibody Technique
Gene Knockdown Techniques
Graft vs Host Disease
Humans
Lung
/ drug effects
MAP Kinase Signaling System
Male
Mice
Mice, Knockout
Middle Aged
Myofibroblasts
Real-Time Polymerase Chain Reaction
Scleroderma, Systemic
/ genetics
Sitagliptin Phosphate
/ pharmacology
Skin
/ drug effects
Transforming Growth Factor beta
Vildagliptin
/ pharmacology
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
05
11
2018
accepted:
23
07
2019
pubmed:
28
7
2019
medline:
18
3
2020
entrez:
28
7
2019
Statut:
ppublish
Résumé
Expression of dipeptidylpeptidase 4 (DPP-4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP-4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP-4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc). Expression of DPP-4 in skin biopsy samples and dermal fibroblasts was analyzed by real-time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP-4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6). The expression of DPP-4 and the number of DPP-4-positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor β (TGFβ)-dependent manner. DPP-4-positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGFβ-induced ERK signaling. DPP4-knockout mice were less sensitive to bleomycin-induced dermal and pulmonary fibrosis (P < 0.0001 versus wild-type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft-versus-host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. DPP-4 characterizes a population of activated fibroblasts and shows that DPP-4 regulates TGFβ-induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well-tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.
Substances chimiques
Dipeptidyl-Peptidase IV Inhibitors
0
Transforming Growth Factor beta
0
Bleomycin
11056-06-7
Collagen
9007-34-5
Dipeptidyl Peptidase 4
EC 3.4.14.5
Vildagliptin
I6B4B2U96P
Sitagliptin Phosphate
TS63EW8X6F
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
137-149Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2019, American College of Rheumatology.
Références
Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009;360:1989-2003.
Ramming A, Dees C, Distler JH. From pathogenesis to therapy: perspective on treatment strategies in fibrotic diseases. Pharmacol Res 2015;100:93-100.
Mizoguchi F, Slowikowski K, Wei K, Marshall JL, Rao DA, Chang SK, et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun 2018;9:789.
Crowley T, O'Neil JD, Adams H, Thomas AM, Filer A, Buckley CD, et al. Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts. Arthritis Res Ther 2017;19:35.
Filer A, Ward LS, Kemble S, Davies CS, Munir H, Rogers R, et al. Identification of a transitional fibroblast function in very early rheumatoid arthritis. Ann Rheum Dis 2017;76:2105-12.
Buckley CD, Barone F, Nayar S, Bénézech C, Caamaño J. Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu Rev Immunol 2015;33:715-45.
Neumann E, Lefèvre S, Zimmermann B, Gay S, Müller-Ladner U. Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol Med 2010;16:458-68.
Sorrell JM, Caplan AI. Fibroblasts: a diverse population at the center of it all. Int Rev Cell Mol Biol 2009;276:161-214.
Palumbo-Zerr K, Soare A, Zerr P, Liebl A, Mancuso R, Tomcik M, et al. Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis. Ann Rheum Dis 2017;76:244-51.
Györfi AH, Matei AE, Distler JH. Targeting TGF-β signaling for the treatment of fibrosis. Matrix Biol 2018;68-9:8-27.
Gorrell MD, Gysbers V, McCaughan GW. CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes. Scand J Immunol 2001;54:249-64.
Klemann C, Wagner L, Stephan M, von Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system. Clin Exp Immunol 2016;185:1-21.
Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev 2014;35:992-1019.
Kim HJ, Kwak WY, Min JP, Sung SY, Kim HD, Kim MK, et al. Dipeptidyl peptidase-4 inhibitor with β-amino amide scaffold: synthesis, SAR and biological evaluation. Bioorg Med Chem Lett 2012;22:5545-9.
Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care 2011;34 Suppl 2:S276-8.
Lambeir AM, Durinx C, Scharpé S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 2003;40:209-94.
Forssmann U, Stoetzer C, Stephan M, Kruschinski C, Skripuletz T, Schade J, et al. Inhibition of CD26/dipeptidyl peptidase IV enhances CCL11/eotaxin-mediated recruitment of eosinophils in vivo. J Immunol 2008;181:1120-7.
Kameoka J, Tanaka T, Nojima Y, Schlossman SF, Morimoto C. Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science 1993;261:466-9.
Kim SC, Schneeweiss S, Glynn RJ, Doherty M, Goldfine AB, Solomon DH. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study. Ann Rheum Dis 2015;74:1968-75.
Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, et al. Skin fibrosis: identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 2015;348:aaa2151.
Van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2013;65:2737-47.
LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573-6.
Marguet D, Baggio L, Kobayashi T, Bernard AM, Pierres M, Nielsen PF, et al. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci U S A 2000;97:6874-9.
Liang R, Šumová B, Cordazzo C, Mallano T, Zhang Y, Wohlfahrt T, et al. The transcription factor GLI2 as a downstream mediator of transforming growth factor-β-induced fibroblast activation in SSc. Ann Rheum Dis 2017;76:756-64.
Chakraborty D, Šumová B, Mallano T, Chen CW, Distler A, Bergmann C, et al. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nat Commun 2017;8:1130.
Matei AE, Beyer C, Györfi AH, Soare A, Chen CW, Dees C, et al. Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators. Ann Rheum Dis 2018;77:459.
Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY, Almirez R, et al. SD-208, a novel transforming growth factor β receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 2004;64:7954-61.
Palumbo-Zerr K, Zerr P, Distler A, Fliehr J, Mancuso R, Huang J, et al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis. Nat Med 2015;21:150-8.
Distler A, Ziemer C, Beyer C, Lin NY, Chen CW, Palumbo-Zerr K, et al. Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling. Ann Rheum Dis 2014;73:624-7.
Zhang Y, Liang R, Chen CW, Mallano T, Dees C, Distler A, et al. JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment. Ann Rheum Dis 2017;76:1467-75.
Soare A, Ramming A, Avouac J, Distler JH. Updates on animal models of systemic sclerosis. J Scleroderma Relat Disord 2016;1:266-76.
Zerr P, Palumbo-Zerr K, Distler A, Tomcik M, Vollath S, Munoz LE, et al. Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood 2012;120:2909-17.
Chen CW, Beyer C, Liu J, Maier C, Li C, Trinh-Minh T, et al. Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling. Ann Rheum Dis 2017;76:773-8.
Marquart S, Zerr P, Akhmetshina A, Palumbo K, Reich N, Tomcik M, et al. Inactivation of the cannabinoid receptor CB1 prevents leukocyte infiltration and experimental fibrosis. Arthritis Rheum 2010;62:3467-76.
Mallano T, Palumbo-Zerr K, Zerr P, Ramming A, Zeller B, Beyer C, et al. Activating transcription factor 3 regulates canonical TGFβ signalling in systemic sclerosis. Ann Rheum Dis 2016;75:586-92.
Huang J, Beyer C, Palumbo-Zerr K, Zhang Y, Ramming A, Distler A, et al. Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis 2016;75:883-90.
Hübner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, et al. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques 2008;44:507-11, 514-7.
Waumans Y, Baerts L, Kehoe K, Lambeir AM, De Meester I. The dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl carboxypeptidase in the immune system and inflammatory disease, including atherosclerosis [review]. Front Immunol 2015;6:387.
Wronkowitz N, Görgens SW, Romacho T, Villalobos LA, Sánchez-Ferrer CF, Peiró C, et al. Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2. Biochim Biophy Acta 2014;1842:1613-21.
Sinnathurai P, Lau W, Vieira de Ribeiro AJ, Bachovchin WW, Englert H, Howe G, et al. Circulating fibroblast activation protein and dipeptidyl peptidase 4 in rheumatoid arthritis and systemic sclerosis. Int J Rheum Dis 2018;21:1915-23.
Beyer C, Distler JH. Tyrosine kinase signaling in fibrotic disorders: translation of basic research to human disease. Biochim Biophys Acta 2013;1832:897-904.
Skhirtladze C, Distler O, Dees C, Akhmetshina A, Busch N, Venalis P, et al. Src kinases in systemic sclerosis: central roles in fibroblast activation and in skin fibrosis. Arthritis Rheum 2008;58:1475-84.
Kaji K, Yoshiji H, Ikenaka Y, Noguchi R, Aihara Y, Douhara A, et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J Gastroenterol 2014;49:481-91.
Esposito G, Cappetta D, Russo R, Rivellino A, Ciuffreda LP, Roviezzo F, et al. Sitagliptin reduces inflammation, fibrosis and preserves diastolic function in a rat model of heart failure with preserved ejection fraction. Br J Pharmacol 2017;174:4070-86.
Wang XM, Holz LE, Chowdhury S, Cordoba SP, Evans KA, Gall MG, et al. The pro-fibrotic role of dipeptidyl peptidase 4 in carbon tetrachloride-induced experimental liver injury. Immunol Cell Biol 2017;95:443-53.
Wohlfahrt T, Usherenko S, Englbrecht M, Dees C, Weber S, Beyer C, et al. Type 2 innate lymphoid cell counts are increased in patients with systemic sclerosis and correlate with the extent of fibrosis. Ann Rheum Dis 2016;75:623-6.
Hatano R, Ohnuma K, Yamamoto J, Dang NH, Morimoto C. CD26-mediated co-stimulation in human CD8(+) T cells provokes effector function via pro-inflammatory cytokine production. Immunology 2013;138:165-72.
Tasic T, Bäumer W, Schmiedl A, Schwichtenhövel F, Pabst R, Raap U, et al. Dipeptidyl peptidase IV (DPP4) deficiency increases Th1-driven allergic contact dermatitis. Clin Exp Allergy 2011;41:1098-107.
Ohnuma K, Takahashi N, Yamochi T, Hosono O, Dang NH, Morimoto C. Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci 2008;13:2299-310.
Yan S, Marguet D, Dobers J, Reutter W, Fan H. Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen. Eur J Immunol 2003;33:1519-27.
Karagiannis T, Boura P, Tsapas A. Safety of dipeptidyl peptidase 4 inhibitors: a perspective review. Ther Adv Drug Saf 2014;5:138-46.