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
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.
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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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Lafyatis, R. Transforming growth factor β—at the centre of systemic sclerosis. Nat Rev Rheumatol 10, 706–719 (2014). https://doi.org/10.1038/nrrheum.2014.137
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