Review Article | Published:

Transforming growth factor β—at the centre of systemic sclerosis

Nature Reviews Rheumatology volume 10, pages 706719 (2014) | Download Citation

Abstract

Transforming growth factor β (TGF-β) has long been implicated in fibrotic diseases, including the multisystem fibrotic disease systemic sclerosis (SSc). Expression of TGF-β-regulated genes in fibrotic skin and lungs of patients with SSc correlates with disease activity, which points to this cytokine as the central mediator of pathogenesis. Patients with SSc often develop pulmonary arterial hypertension (PAH), a particularly lethal complication caused by vascular dysfunction. Several genetic diseases with vascular features related to SSc, such as familial PAH and hereditary haemorrhagic telangiectasia, are caused by mutations in the TGF-β-sensing ALK-1 signalling pathway. These observations suggest that increased TGF-β signalling causes both vascular and fibrotic features of SSc. The question of how latent TGF-β becomes activated in local SSc tissues is, therefore, central to the understanding of SSc. Both TGF-β1 and TGF-β3 can be activated by integrins αvβ6 and αvβ8, whose upregulation in bronchial epithelial cells can activate TGF-β in SSc lungs. Other αv integrins, thrombospondin-1 or altered TGF-β sequestration by matrix proteins might be important in other target tissues. How the immune system triggers this process remains unclear, although links between inflammation and TGF-β activation are emerging. Together, these observations provide an increasingly secure framework for understanding TGF-β in SSc pathogenesis.

Key points

  • Transforming growth factor β (TGF-β) superfamily members are pleotropic cytokines that regulate fibrosis, inflammation and vascular biology, all key aspects of systemic sclerosis (SSc) pathogenesis

  • Emerging data have shown that integrins, proteases and altered connective tissue sequestration can regulate activation of latent TGF-β and provide possible mechanisms for TGF-β-mediated fibrosis in SSc

  • SSc is characterized by prominent vascular features also seen in familial pulmonary arterial hypertension and hereditary haemorrhagic telangiectasia, both of which are associated with mutations in proteins involved in TGF-β and bone morphogenetic protein signalling

  • Immune cells such as dendritic cells and macrophages can activate TGF-β in SSc through surface integrins or upon ingestion of apoptotic or necrotic cells, respectively

  • Effects of TGF-β activation on immune cells include dampened T helper 1 and T helper 2 responses, increased regulatory T cell and T helper 17 cell differentiation and augmented leukocyte infiltration

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References

  1. 1.

    et al. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

  2. 2.

    et al. Defective haematopoiesis and vasculogenesis in transforming growth factor-β 1 knock out mice. Development 121, 1845–1854 (1995).

  3. 3.

    et al. Transforming growth factor-β3 is required for secondary palate fusion. Nat. Genet. 11, 409–414 (1995).

  4. 4.

    et al. Abnormal lung development and cleft palate in mice lacking TGF-β3 indicates defects of epithelial-mesenchymal interaction. Nat. Genet. 11, 415–421 (1995).

  5. 5.

    et al. TGFβ2 knockout mice have multiple developmental defects that are non-overlapping with other TGFβ knockout phenotypes. Development 124, 2659–2670 (1997).

  6. 6.

    et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat. Genet. 44, 916–921 (2012).

  7. 7.

    et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat. Genet. 44, 922–927 (2012).

  8. 8.

    & BMP signaling in vascular development and disease. Cytokine Growth Factor Rev. 21, 287–298 (2010).

  9. 9.

    , , & BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition in human renal proximal tubular epithelial cells. J. Nephrol. 22, 403–410 (2009).

  10. 10.

    & Unchaining the beast; insights from structural and evolutionary studies on TGFβ secretion, sequestration, and activation. Cytokine Growth Factor Rev. 24, 355–372 (2013).

  11. 11.

    et al. Fibrillin-1 microfibril deposition is dependent on fibronectin assembly. J. Cell. Sci. 121, 2696–2704 (2008).

  12. 12.

    et al. Assembly of fibrillin microfibrils governs extracellular deposition of latent TGFβ. J. Cell. Sci. 123, 3006–3018 (2010).

  13. 13.

    et al. Latent transforming growth factor β-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J. Biol. Chem. 278, 2750–2757 (2003).

  14. 14.

    et al. Specificity of latent TGF-β binding protein (LTBP) incorporation into matrix: role of fibrillins and fibronectin. J. Cell. Physiol. 227, 3828–3836 (2012).

  15. 15.

    et al. Immunohistological demonstration of transforming growth factor-β isoforms in the skin of patients with systemic sclerosis. Clin. Immunol. Immunopathol. 69, 199–204 (1993).

  16. 16.

    et al. Immunocytochemical localization and serologic detection of transforming growth factor β1. Association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud's phenomenon. Arthritis Rheum. 37, 278–288 (1994).

  17. 17.

    & The roles of transforming growth factor type β3 (TGF-β3) and mast cells in the pathogenesis of scleroderma. Clin. Rheumatol. 22, 189–195 (2003).

  18. 18.

    , , , & Circulating levels of active transforming growth factor β1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score. Rheumatology (Oxford) 44, 1518–1524 (2005).

  19. 19.

    et al. Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 56, 323–333 (2007).

  20. 20.

    et al. Association of interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheum. 66, 714–725 (2014).

  21. 21.

    , , & A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 62, 580–588 (2010).

  22. 22.

    , & Myofibroblasts and hyalinized collagen as markers of skin disease in systemic sclerosis. Arthritis Rheum. 54, 3655–3660 (2006).

  23. 23.

    et al. Increase in fibronectin in the deep dermis of involved skin in progressive systemic sclerosis. Arthritis Rheum. 22, 983–987 (1979).

  24. 24.

    , , & Extracellular microfibrils are increased in localized and systemic scleroderma skin. Lab. Invest. 64, 791–798 (1991).

  25. 25.

    , , & Transforming growth factor β induces fibroblast fibrillin-1 matrix formation. Arthritis Rheum. 46, 3000–3009 (2002).

  26. 26.

    , & Augmented production of transforming growth factor-β by cultured peripheral blood mononuclear cells from patients with systemic sclerosis. Arch. Dermatol. Res. 296, 89–93 (2004).

  27. 27.

    et al. Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice. J. Cell Biol. 176, 787–793 (2007).

  28. 28.

    , , , & Integrin-mediated transforming growth factor-β activation regulates homeostasis of the pulmonary epithelial-mesenchymal trophic unit. Am. J. Pathol. 169, 405–415 (2006).

  29. 29.

    et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).

  30. 30.

    , , & Integrin αVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J. Cell Biol. 165, 723–734 (2004).

  31. 31.

    et al. Partial inhibition of integrin α(v)β6 prevents pulmonary fibrosis without exacerbating inflammation. Am. J. Respir. Crit. Care Med. 177, 56–65 (2008).

  32. 32.

    et al. The integrin α(v)β8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1. J. Cell Biol. 157, 493–507 (2002).

  33. 33.

    et al. Interleukin-1β induces increased transcriptional activation of the transforming growth factor-β-activating integrin subunit β8 through altering chromatin architecture. J. Biol. Chem. 286, 36864–36874 (2011).

  34. 34.

    et al. β8 integrins are required for vascular morphogenesis in mouse embryos. Development 129, 2891–2903 (2002).

  35. 35.

    et al. Integrin α(v)β8-mediated activation of transforming growth factor-β by perivascular astrocytes: an angiogenic control switch. Am. J. Pathol. 166, 1883–1894 (2005).

  36. 36.

    , , , & TGFβ1 and TGFβ3 are partially redundant effectors in brain vascular morphogenesis. Mech. Dev. 125, 508–516 (2008).

  37. 37.

    et al. Loss of integrin α(v)β8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).

  38. 38.

    , , , & Increased expression of integrin αvβ5 induces the myofibroblastic differentiation of dermal fibroblasts. Am. J. Pathol. 168, 499–510 (2006).

  39. 39.

    , , , & Involvement of αvβ5 integrin in the establishment of autocrine TGF-β signaling in dermal fibroblasts derived from localized scleroderma. J. Invest. Dermatol. 126, 1761–1769 (2006).

  40. 40.

    et al. Increased expression of integrin α(v)β3 contributes to the establishment of autocrine TGF-β signaling in scleroderma fibroblasts. J. Immunol. 175, 7708–7718 (2005).

  41. 41.

    et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19, 1617–1624 (2013).

  42. 42.

    et al. Expression of integrin β1 by fibroblasts is required for tissue repair in vivo. J. Cell Sci. 123, 3674–3682 (2010).

  43. 43.

    , , , & Loss of β1 integrin in mouse fibroblasts results in resistance to skin scleroderma in a mouse model. Arthritis Rheum. 60, 2817–2821 (2009).

  44. 44.

    et al. Regulation of transforming growth factor-β activation by discrete sequences of thrombospondin 1. J. Biol. Chem. 270, 7304–7310 (1995).

  45. 45.

    et al. Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 93, 1159–1170 (1998).

  46. 46.

    et al. Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-β signaling in cultured scleroderma fibroblasts. Am. J. Pathol. 166, 1451–1463 (2005).

  47. 47.

    , , & Production of recombinant proteins in Chinese hamster ovary cells overexpressing the subtilisin-like proprotein converting enzyme furin. Mol. Biol. Rep. 23, 87–95 (1996).

  48. 48.

    et al. Evidence that furin is an authentic transforming growth factor-β1-converting enzyme. Am. J. Pathol. 158, 305–316 (2001).

  49. 49.

    , , & Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol. Carcinog. 44, 151–161 (2005).

  50. 50.

    et al. Latent TGF-β1 activation by platelets. J. Cell. Physiol. 199, 67–76 (2004).

  51. 51.

    , , & Mechanism of activation of latent recombinant transforming growth factor β 1 by plasmin. J. Cell Biol. 110, 1361–1367 (1990).

  52. 52.

    The role of proteases in transforming growth factor-β activation. Int. J. Biochem. Cell Biol. 40, 1068–1078 (2008).

  53. 53.

    , , , & Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-βL a process initiated by the exocytosis of cathepsin B. J. Biol. Chem. 277, 14829–14837 (2002).

  54. 54.

    et al. Ligation of protease-activated receptor 1 enhances α(v)β6 integrin-dependent TGF-β activation and promotes acute lung injury. J. Clin. Invest. 116, 1606–1614 (2006).

  55. 55.

    et al. Matrix metalloproteinase 2 activation of transforming growth factor-β1 (TGF-β1) and TGF-β1-type II receptor signaling within the aged arterial wall. Arterioscler. Thromb. Vasc. Biol. 26, 1503–1509 (2006).

  56. 56.

    & Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000).

  57. 57.

    & BMP1 controls TGFβ1 activation via cleavage of latent TGFβ-binding protein. J. Cell Biol. 175, 111–120 (2006).

  58. 58.

    et al. Matrix metalloproteinase-dependent activation of latent transforming growth factor-β controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J. Biol. Chem. 277, 44061–44067 (2002).

  59. 59.

    et al. PGE2 induces angiogenesis via MT1-MMP-mediated activation of the TGFβ/Alk5 signaling pathway. Blood 112, 1120–1128 (2008).

  60. 60.

    et al. Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma. Proc. Natl Acad. Sci. USA 107, 14170–14175 (2010).

  61. 61.

    et al. Impaired liver regeneration in mice by lipopolysaccharide via TNF-α/kallikrein-mediated activation of latent TGF-β. Gastroenterology 123, 352–364 (2002).

  62. 62.

    et al. Increased circulating levels of tissue kallikrein in systemic sclerosis correlate with microvascular involvement. Ann. Rheum. Dis. 64, 382–387 (2005).

  63. 63.

    et al. Elevated matrix metalloproteinase-9 in patients with systemic sclerosis. Arthritis Res. Ther. 7, R71–R79 (2005).

  64. 64.

    , , & Binding of anti-SSA antibodies to apoptotic fetal cardiocytes stimulates urokinase plasminogen activator (uPA)/uPA receptor-dependent activation of TGF-β and potentiates fibrosis. J. Immunol. 187, 5392–5401 (2011).

  65. 65.

    , , & Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).

  66. 66.

    & Integrins and the activation of latent transforming growth factor β1—an intimate relationship. Eur. J. Cell Biol. 87, 601–615 (2008).

  67. 67.

    & in Hochberg: Rheumatology 6th edn Vol. 2 Ch. Etiology and Pathogenesis of Systemic Sclerosis (eds Hochberg, M. C. et al.) 1387–1402 (Mosby, 2014).

  68. 68.

    , , & Scleroderma renal crisis: a pathology perspective. Int. J. Rheumatol. 2010, 543704 (2010).

  69. 69.

    Pulmonary hypertension: pathology. Handb. Exp. Pharmacol. 218, 59–75 (2013).

  70. 70.

    et al. Modern age pathology of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med 186, 261–272 (2012).

  71. 71.

    & State of the art on nailfold capillaroscopy: a reliable diagnostic tool and putative biomarker in rheumatology? Rheumatology (Oxford) 52, 1933–1940 (2013).

  72. 72.

    et al. Negative regulation of inducible nitric-oxide synthase expression mediated through transforming growth factor-β-dependent modulation of transcription factor TCF11. J. Biol. Chem. 282, 36837–36844 (2007).

  73. 73.

    , , & Abnormalities in the regulators of angiogenesis in patients with scleroderma. J. Rheumatol. 36, 576–582 (2009).

  74. 74.

    et al. Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis. Circ. Res. 109, e14–e26 (2011).

  75. 75.

    , , , & Sensitivity of different vascular beds in the eye to neovascularization and blood-retinal barrier breakdown in VEGF transgenic mice. Adv. Exp. Med. Biol. 476, 129–138 (2000).

  76. 76.

    et al. Circulating endothelin-1 levels in systemic sclerosis subsets—a marker of fibrosis or vascular dysfunction? J. Rheumatol. 21, 1838–1844 (1994).

  77. 77.

    et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 50, 3985–3993 (2004).

  78. 78.

    et al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med 346, 896–903 (2002).

  79. 79.

    , , , & Inhibitory action of transforming growth factor β on endothelial cells. Proc. Natl Acad. Sci. USA 84, 5600–5604 (1987).

  80. 80.

    et al. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nat. Genet. 26, 81–84 (2000).

  81. 81.

    et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family. J. Med. Genet. 37, 741–745 (2000).

  82. 82.

    et al. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation 118, 722–730 (2008).

  83. 83.

    et al. Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. Circ. Res. 97, 496–504 (2005).

  84. 84.

    et al. Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J. 21, 1743–1753 (2002).

  85. 85.

    , , , & Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109, 1953–1961 (2007).

  86. 86.

    et al. Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J. 23, 4018–4028 (2004).

  87. 87.

    , & Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J. Invest. Dermatol. 95, 422–427 (1990).

  88. 88.

    et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N. Engl. J. Med. 345, 325–334 (2001).

  89. 89.

    et al. Transforming growth factor-β receptor mutations and pulmonary arterial hypertension in childhood. Circulation 111, 435–441 (2005).

  90. 90.

    et al. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J. Cell Sci. 120, 964–972 (2007).

  91. 91.

    et al. TGFβ receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients. Ann. Rheum. Dis. 71, 1900–1903 (2012).

  92. 92.

    et al. A clue for telangiectasis in systemic sclerosis: elevated serum soluble endoglin levels in patients with the limited cutaneous form of the disease. Dermatology 213, 88–92 (2006).

  93. 93.

    et al. Direct transfer of transforming growth factor β 1 gene into arteries stimulates fibrocellular hyperplasia. Proc. Natl Acad. Sci. USA 90, 10759–10763 (1993).

  94. 94.

    et al. Endothelial injury in a transforming growth factor β-dependent mouse model of scleroderma induces pulmonary arterial hypertension. Arthritis Rheum. 65, 2928–2939 (2013).

  95. 95.

    & Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb. Perspect. Med. 2, a006627 (2012).

  96. 96.

    et al. Type β transforming growth factor: a bifunctional regulator of cellular growth. Proc. Natl Acad. Sci. USA 82, 119–123 (1985).

  97. 97.

    et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA 83, 4167–4171 (1986).

  98. 98.

    , , & Transforming growth factor-β. Major role in regulation of extracellular matrix. Ann. NY Acad. Sci. 580, 225–232 (1990).

  99. 99.

    , & Transforming growth factor β increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability. Proc. Natl Acad. Sci. USA 85, 1105–1108 (1988).

  100. 100.

    , , & Therapy for fibrotic diseases: nearing the starting line. Sci. Transl. Med. 5, 167sr1 (2013).

  101. 101.

    et al. Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis. Exp. Mol. Pathol. 83, 39–46 (2007).

  102. 102.

    , & Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J. Invest. Dermatol. 121, 713–719 (2003).

  103. 103.

    The myofibroblast in wound healing and fibrocontractive diseases. J. Pathol. 200, 500–503 (2003).

  104. 104.

    et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

  105. 105.

    et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc. Natl Acad. Sci. USA 103, 13180–13185 (2006).

  106. 106.

    et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).

  107. 107.

    et al. Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis. Am. J. Pathol. 182, 118–131 (2013).

  108. 108.

    et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 188, 820–830 (2013).

  109. 109.

    , , , & Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat. Med. 18, 1262–1270 (2012).

  110. 110.

    et al. A pericyte origin of spinal cord scar tissue. Science 333, 238–242 (2011).

  111. 111.

    et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).

  112. 112.

    , , , & Activation of microvascular pericytes in autoimmune Raynaud's phenomenon and systemic sclerosis. Arthritis Rheum. 42, 930–941 (1999).

  113. 113.

    , , & Transforming growth factor-β 1 induces α-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122, 103–111 (1993).

  114. 114.

    et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: potential role in idiopathic pulmonary fibrosis. Am. J. Pathol. 166, 1321–1332 (2005).

  115. 115.

    et al. Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor β. Ann. Rheum. Dis. 68, 435–441 (2009).

  116. 116.

    , & Fibrillin in Marfan syndrome and tight skin mice provides new insights into transforming growth factor-β regulation and systemic sclerosis. Curr. Opin. Rheumatol. 18, 582–587 (2006).

  117. 117.

    et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407–411 (2003).

  118. 118.

    et al. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci. Transl. Med. 2, 23ra20 (2010).

  119. 119.

    et al. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 503, 126–130 (2013).

  120. 120.

    et al. Endoglin promotes TGF-β/Smad1 signaling in scleroderma fibroblasts. J. Cell. Physiol. 226, 3340–3348 (2011).

  121. 121.

    , , , & Transforming growth factor-β receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways. J. Biol. Chem. 282, 10405–10413 (2007).

  122. 122.

    , & CCN2 is required for the TGF-β induced activation of Smad1-Erk1/2 signaling network. PLoS ONE 6, e21911 (2011).

  123. 123.

    et al. Contribution of activin receptor-like kinase 5 (transforming growth factor β receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts. Arthritis Rheum. 54, 1309–1316 (2006).

  124. 124.

    et al. Smad-independent transforming growth factor-β regulation of early growth response-1 and sustained expression in fibrosis: implications for scleroderma. Am. J. Pathol. 173, 1085–1099 (2008).

  125. 125.

    et al. Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing. Am. J. Pathol. 175, 1041–1055 (2009).

  126. 126.

    et al. A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate. Oncogene 28, 1285–1297 (2009).

  127. 127.

    Noncanonical transforming growth factor β signaling in scleroderma fibrosis. Curr. Opin. Rheumatol. 21, 623–629 (2009).

  128. 128.

    & Systemic sclerosis: a prototypic multisystem fibrotic disorder. J. Clin. Invest. 117, 557–567 (2007).

  129. 129.

    & (Eds) The TGF-β Family 8th edn (Cold Spring Harbor Laboratory Press, 2007).

  130. 130.

    et al. Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am. J. Hum. Genet. 94, 47–61 (2014).

  131. 131.

    et al. A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists. Arthritis Rheum. 56, 1010–1020 (2007).

  132. 132.

    , , , & Regulation of TGFβ in the immune system: an emerging role for integrins and dendritic cells. Immunobiology 217, 1259–1265 (2012).

  133. 133.

    et al. αv β6 integrin regulates renal fibrosis and inflammation in Alport mouse. Am. J. Pathol. 170, 110–125 (2007).

  134. 134.

    et al. Inhibition of integrin α(v)β6, an activator of latent transforming growth factor-β, prevents radiation-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 177, 82–90 (2008).

  135. 135.

    et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β. J. Clin. Invest. 121, 2863–2875 (2011).

  136. 136.

    et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β(1). J. Exp. Med. 194, 809–821 (2001).

  137. 137.

    , , , & TGF-β 1 and IFN-gamma direct macrophage activation by TNF-α to osteoclastic or cytocidal phenotype. J. Immunol. 165, 4957–4963 (2000).

  138. 138.

    , , , & Modulation of macrophage efferocytosis in inflammation. Front. Immunol. 2, 57 (2011).

  139. 139.

    , , & Apoptotic cells and innate immune stimuli combine to regulate macrophage cytokine secretion. J. Immunol. 171, 2610–2615 (2003).

  140. 140.

    , & Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation. J. Clin. Invest. 109, 41–50 (2002).

  141. 141.

    et al. Regulation of the expression of GARP/latent TGF-β1 complexes on mouse T cells and their role in regulatory T cell and Th17 differentiation. J. Immunol. 190, 5506–5515 (2013).

  142. 142.

    et al. Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFβ expression. PLoS ONE 4, e5981 (2009).

  143. 143.

    et al. The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFβ and IFNgamma distinguishes SSc phenotypes. PLoS ONE 4, e5903 (2009).

  144. 144.

    et al. Transforming growth factor type β induces monocyte chemotaxis and growth factor production. Proc. Natl Acad. Sci. USA 84, 5788–5792 (1987).

  145. 145.

    , , & Latent TGFβ1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J. 23, 1770–1781 (2004).

  146. 146.

    et al. Inflammatory skin disease in K5.hTGF-β1 transgenic mice is not dependent on the IL-23/Th17 inflammatory pathway. J. Invest. Dermatol. 129, 2443–2450 (2009).

  147. 147.

    et al. Global chemokine expression in systemic sclerosis (SSc): CCL19 expression correlates with vascular inflammation in SSc skin. Ann. Rheum. Dis. (2013).

  148. 148.

    et al. Mice that lack activity of αvβ6- and αvβ8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice. J. Cell Sci. 122, 227–232 (2009).

  149. 149.

    et al. Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis. Arthritis Rheum. 62, 1523–1532 (2010).

  150. 150.

    , , , & CTGF mediates Smad-dependent transforming growth factor β signaling to regulate mesenchymal cell proliferation during palate development. Mol. Cell. Biol. 33, 3482–3493 (2013).

  151. 151.

    , , & CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. J. Clin. Invest. 120, 3340–3349 (2010).

  152. 152.

    et al. Connective tissue growth factor inhibits adipocyte differentiation. Am. J. Physiol. Cell Physiol. 295, C740–C751 (2008).

  153. 153.

    et al. ALK-5 mediates endogenous and TGF-β1-induced expression of connective tissue growth factor in embryonic lung. Am. J. Respir. Cell Mol. Biol. 36, 552–561 (2007).

  154. 154.

    , , & Smad3 and extracellular signal-regulated kinase 1/2 coordinately mediate transforming growth factor-β-induced expression of connective tissue growth factor in human fibroblasts. J. Invest. Dermatol. 124, 1162–1169 (2005).

  155. 155.

    , , , & Therapeutic value of small molecule inhibitor to plasminogen activator inhibitor-1 for lung fibrosis. Am. J. Respir. Cell Mol. Biol. 46, 87–95 (2012).

  156. 156.

    et al. Genetic deficiency of plasminogen activator inhibitor-1 promotes cardiac fibrosis in aged mice: involvement of constitutive transforming growth factor-β signaling and endothelial-to-mesenchymal transition. Circulation 122, 1200–1209 (2010).

  157. 157.

    et al. Source of early reactive oxygen species in the apoptosis induced by transforming growth factor-β in fetal rat hepatocytes. Free Radic. Biol. Med. 36, 16–26 (2004).

  158. 158.

    et al. Modulation of collagen type I, fibronectin and dermal fibroblast function and activity, in systemic sclerosis by the antioxidant epigallocatechin-3-gallate. Rheumatology (Oxford) 49, 2024–2036 (2010).

  159. 159.

    et al. An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model. Am. J. Respir. Cell Mol. Biol. 50, 158–169 (2014).

  160. 160.

    et al. Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. Arthritis Rheum. 66, 1010–1021 (2014).

  161. 161.

    , , & Regulated expression of cadherin-11 in human extravillous cytotrophoblasts undergoing aggregation and fusion in response to transforming growth factor β1. J. Reprod. Fertil. 114, 357–363 (1998).

  162. 162.

    et al. Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-β production and epithelial to mesenchymal transition. FASEB J. 26, 503–512 (2012).

  163. 163.

    et al. Endothelin is a downstream mediator of profibrotic responses to transforming growth factor β in human lung fibroblasts. Arthritis Rheum. 56, 4189–4194 (2007).

  164. 164.

    et al. The interaction of endothelin-1 and TGF-β1 mediates vascular cell remodeling. PLoS ONE 8, e73399 (2013).

  165. 165.

    et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 184, 92–99 (2011).

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  1. Boston University School of Medicine, E5 Arthritis Centre, 72 E. Concord Street, Boston, MA 02118, USA.

    • Robert Lafyatis

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Competing interests

R.L. declares that he has acted as a consultant for Actelion, Akros, Amira, Biogen, Bristol Myers Squibb, Celdara, Celgene, Celltex, Dart Therapeutics, EMD Serono, Genentech, Genzyme, Idera, Inception, Intermune, Lycera, Medimmune, Novartis, Precision Dermatology, PRISM, Promedior, Regeneron, Roche, Sanofi, Aventis, Shire, UCB and Zwitter, and that he has received grants from Genentech, Genzyme, Human Genome Sciences, Regeneron, Sanofi, Shire, and UCB.

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Correspondence to Robert Lafyatis.

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https://doi.org/10.1038/nrrheum.2014.137

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