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Another Piece in the Fibrotic Puzzle: TSLP as a Novel Ligand for Fibrocyte Activation

2016; Elsevier BV; Volume: 136; Issue: 2 Linguagem: Inglês

10.1016/j.jid.2015.11.014

1523-1747

Romy Christmann,

Cytokine Signaling Pathways and Interactions

Thymic stromal lymphopoietin (TSLP) has emerged as an important cytokine in the pathogenesis of nonallergic diseases, especially in diseases that include fibrosis. It has been shown to be upregulated in both cutaneous and lung fibrotic conditions. Shin et al. report that TSLP may also play a role in the pathogenesis of keloids. The main mechanism of TSLP profibrotic effects is not as yet fully understood, although the data suggest that it involves collagen production through transforming growth factor-β, at least in the case of dermal fibroblasts. The authors also report that TSLP is able to activate fibrocytes, probably by inducing stromal cell–derived factor-1 (also termed CXCL12), one of its main ligands. These findings support the concept that TSLP plays a role in the development of fibrosis, and they should lead to mechanistic studies on TSLP profibrotic signaling. Thymic stromal lymphopoietin (TSLP) has emerged as an important cytokine in the pathogenesis of nonallergic diseases, especially in diseases that include fibrosis. It has been shown to be upregulated in both cutaneous and lung fibrotic conditions. Shin et al. report that TSLP may also play a role in the pathogenesis of keloids. The main mechanism of TSLP profibrotic effects is not as yet fully understood, although the data suggest that it involves collagen production through transforming growth factor-β, at least in the case of dermal fibroblasts. The authors also report that TSLP is able to activate fibrocytes, probably by inducing stromal cell–derived factor-1 (also termed CXCL12), one of its main ligands. These findings support the concept that TSLP plays a role in the development of fibrosis, and they should lead to mechanistic studies on TSLP profibrotic signaling. Clinical Implications•Thymic stromal lymphopoietin (TSLP) expression is increased in keloid tissue, and it is expressed primarily in alpha smooth muscle cells and myofibroblasts.•TSLP induces collagen and stromal cell–derived factor-1 (SDF-1) production in fibroblasts through a transforming growth factor-β–dependent pathway.•TSLP/SDF-1/CXCR4 signaling should become a topic for research in the fibrotic diseases.Keloid formation is a localized fibrotic skin disease of considerable cosmetic concern, with significant morbidity, high recurrence rates, but with unknown pathogenesis. Several mechanisms have been proposed to play roles in the development of keloids. Shin et al., 2016Shin J.U. Kim S.H. Kim H. Noh J.Y. Jin S. Park C.O. et al.TSLP is a potential initiator of collagen synthesis and an activator of CXCR4/SDF-1 axis in keloid pathogenesis.J Invest Derm. 2016; 136: 507-515Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar report novel pathways that play roles in this complex disease. •Thymic stromal lymphopoietin (TSLP) expression is increased in keloid tissue, and it is expressed primarily in alpha smooth muscle cells and myofibroblasts.•TSLP induces collagen and stromal cell–derived factor-1 (SDF-1) production in fibroblasts through a transforming growth factor-β–dependent pathway.•TSLP/SDF-1/CXCR4 signaling should become a topic for research in the fibrotic diseases. Thymic stromal lymphopoietin (TSLP) is an interleukin 7–like cytokine, and although it has some similarities with IL-7, it has distinct biological functions. Both are vital for B lymphocyte activation, but TSLP is key in the Th2 immune response, having a well-established role as a master regulator of allergic diseases in humans and mice. Most recently, TSLP has also been identified as playing roles in fibrosis and other nonallergic diseases (Ying et al., 2015Ying G. Zhang Y. Tang G. Chen S. Functions of thymic stromal lymphopoietin in non-allergic diseases.Cell Immunol. 2015; 295: 144-149Crossref PubMed Scopus (10) Google Scholar). For example, in systemic sclerosis, an autoimmune disease, it is highly expressed in perivascular areas and in immune CD163+ cells of the skin (Christmann et al., 2013Christmann R.B. Mathes A. Affandi A.J. Padilla C. Nazari B. Bujor A.M. et al.Thymic stromal lymphopoietin is up-regulated in the skin of patients with systemic sclerosis and induces profibrotic genes and intracellular signaling that overlap with those induced by interleukin-13 and transforming growth factor β.Arthritis Rheum. 2013; 65: 1335-1346Crossref PubMed Scopus (48) Google Scholar). TSLP is also upregulated in cutaneous epithelial cells, mast cells, and fibroblasts of patients with systemic sclerosis, and TSLP receptor–deficient mice were partially protected in a bleomycin-induced skin fibrosis model (Usategui et al., 2013Usategui A. Criado G. Izquierdo E. Del Rey M.J. Carreira P.E. Ortiz P. et al.A profibrotic role for thymic stromal lymphopoietin in systemic sclerosis.Ann Rheum Dis. 2013; 72: 2018-2023Crossref PubMed Scopus (38) Google Scholar). In addition, TSLP and its receptor were also strongly expressed in the lungs of patients with idiopathic pulmonary fibrosis, a severe fibrotic lung disease (Datta et al., 2013Datta A. Alexander R. Sulikowski M.G. Nicholson A.G. Maher T.M. Scotton C.J. et al.Evidence for a functional thymic stromal lymphopoietin signaling axis in fibrotic lung disease.J Immunol. 2013; 191: 4867-4879Crossref PubMed Scopus (48) Google Scholar). Fibroblasts were reported to produce TSLP, followed by fibroblast CCL2 release and subsequent monocyte chemotaxis. Shin et al., 2016Shin J.U. Kim S.H. Kim H. Noh J.Y. Jin S. Park C.O. et al.TSLP is a potential initiator of collagen synthesis and an activator of CXCR4/SDF-1 axis in keloid pathogenesis.J Invest Derm. 2016; 136: 507-515Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar reported the strong expression of TSLP in keloidal tissues, another fibrotic skin disease. With respect to the fibrotic effect of TSLP, our group observed that injection of TSLP into the skin of mice caused upregulation of a cluster of genes, overlapping with IL-13 and transforming growth factor-β (TGF-β). This complex signature was only partially dependent on IL-13 signaling, whereas TSLP-deficient mice treated with TGF-β showed less fibrosis. Our group observed a clear dual effect with proinflammatory and profibrotic signatures in vitro and in vivo (Christmann et al., 2013Christmann R.B. Mathes A. Affandi A.J. Padilla C. Nazari B. Bujor A.M. et al.Thymic stromal lymphopoietin is up-regulated in the skin of patients with systemic sclerosis and induces profibrotic genes and intracellular signaling that overlap with those induced by interleukin-13 and transforming growth factor β.Arthritis Rheum. 2013; 65: 1335-1346Crossref PubMed Scopus (48) Google Scholar). Another piece of the puzzle that Shin et al., 2016Shin J.U. Kim S.H. Kim H. Noh J.Y. Jin S. Park C.O. et al.TSLP is a potential initiator of collagen synthesis and an activator of CXCR4/SDF-1 axis in keloid pathogenesis.J Invest Derm. 2016; 136: 507-515Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar revealed was that the profibrotic effect of TSLP seems to be dependent on TGF-β, at least in dermal fibroblasts. The question still remains concerning whether TSLP profibrotic effects are TGF-β dependent in vivo, although our unpublished studies are pointing to the same direction. The most intriguing aspect of Shin's study is the novel role of TSLP in inducing stromal cell–derived factor-1 (SDF-1) expression in vitro in fibroblasts and in vivo in TSLP-treated mice. These findings suggest TSLP as a novel ligand for SDF-1/CXCR4 signaling, which is involved in recruiting CXCR4+ fibrocytes, a well-known profibrotic cell type, into tissues. One of the main functions of the CXC chemokine receptor (CXCR4) is related to the homing of progenitor cells into the bone marrow. CXCR4 is an evolutionary conserved protein, and it is expressed ubiquitously in many organs. CXCR4's best-known ligand is SDF-1 (chemokine CXCL12), which is also highly conserved between humans and mice. Upon conditions of stress or injury the SDF-1/CXCR4 axis is key in the homing of hematopoietic stem and progenitor cells in the bone marrow, and their mobilization to the periphery. It also affects hematopoietic development, angiogenesis, and even tumor progression. However, CXCR4-mediated signaling has been shown to be more complex than first believed, with two new recently described ligands and a newly recognized receptor that can evoke an SDF-1 signaling that is independent from CXCR4 (Pawig et al., 2015Pawig L. Klasen C. Weber C. Bernhagen J. Noels H. Diversity and inter-connections in the CXCR4 chemokine receptor/ligand family: molecular perspectives.Front Immunol. 2015; 6: 429Crossref PubMed Scopus (121) Google Scholar). TGF-β is a multifunctional cytokine that modulates a broad range of events including wound healing, chemotaxis, angiogenesis, and extracellular matrix deposition. TGF-β is key in the pathogenesis of almost all fibrotic diseases, and recently, it has been described as upregulating CXCR4 expression in several cell types, including endothelial cells and myofibroblasts (Feng et al., 2014Feng Y.F. Yuan F. Guo H. Wu W.Z. TGF-β1 enhances SDF-1-induced migration and tube formation of choroid-retinal endothelial cells by up-regulating CXCR4 and CXCR7 expression.Mol Cell Biochem. 2014; 397: 131-138Crossref PubMed Scopus (24) Google Scholar). Shin et al., 2016Shin J.U. Kim S.H. Kim H. Noh J.Y. Jin S. Park C.O. et al.TSLP is a potential initiator of collagen synthesis and an activator of CXCR4/SDF-1 axis in keloid pathogenesis.J Invest Derm. 2016; 136: 507-515Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar show that the CXCR4/SDF-1 axis is upregulated in keloids, reinforcing the concept of a critical role for this pathway in skin fibrosis. SDF-1 and CXCR4 have been shown to be upregulated in other cutaneous and lung fibrotic conditions. The authors confirm that most of CD45+ procollagen type 1+ cells, called fibrocytes, co-expressed CXCR4 in keloidal tissues and that they were rarely observed in normal skin. More importantly, the authors describe a novel property of TSLP that suggests its involvement in the development of fibrosis: TSLP can induce the expression of SDF-1 in vivo and in vitro. This effect was correlated with a higher infiltration of CXCR4+ fibrocytes in TSLP-treated mice, which, in turn, might activate the CXCR4/SDF-1 axis, leading to increased skin remodeling. Fibrocytes are bone marrow–derived progenitor cells that are believed to originate from a monocyte precursor. These cells are characterized by cell surface proteins, collagens, and extracellular matrix components. The hematopoietic origin of fibrocytes is reflected by the CD45 and leukocyte-specific protein-1 expression, and their proposed monocytic origin is based on the expression of CD11b, CD11c, and CD11d. Their immunologic properties are reflected by the expression of chemokine receptors, such as CXCR4, and by several antigen presentation markers. Circulating and cultured fibrocytes express CD34, a motility protein that identifies specific stem cell populations. Functionally, fibrocytes are able to produce an array of extracellular matrix components including collagens, interleukins, chemokines, and soluble mediators. Chemokines and growth factors have been described to induce fibrocyte migration into injured tissues, such as SDF-1/CXCR4 axis proteins, leading to several effects, including inflammation and extracellular matrix component production (Kojima et al., 2010Kojima Y. Acar A. Eaton E.N. Mellody K.T. Scheel C. Ben-Porath I. et al.Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts.Proc Natl Acad Sci USA. 2010; 107: 20009-20014Crossref PubMed Scopus (581) Google Scholar, Peng and Herzog, 2012Peng H. Herzog E.L. Fibrocytes: emerging effector cells in chronic inflammation.Curr Opin Pharmacol. 2012; 12: 491-496Crossref PubMed Scopus (56) Google Scholar). Activated fibrocytes have been shown to have a role in tissue remodeling responses, including airway remodeling in asthma, interstitial pulmonary fibrosis, systemic fibrosis such as that occurs in systemic sclerosis and nephrogenic fibrosis, atherosclerosis, and enhanced tumor invasion. In addition to their profibrotic properties, fibrocytes can produce proinflammatory mediators, as well. They can respond to interleukin-1 beta (IL-1b) and to IL17A by secreting IL-6, IL-8, chemokine (C-C motif) ligand 2 (CCL2), CCL3, and other mediators, and they can respond to Th2 cytokines by producing collagen. Finally, fibrocytes produce other extracellular matrix products, including hyaluronan and versican, soluble mediators such as platelet-derived growth factor and TGF-β1, and vascular mediators such as matrix metalloproteinases, vascular endothelial growth factor, platelet-derived growth factor -A, and hepatocyte growth factor (Bucala, 2012Bucala R. Review series—inflammation & fibrosis.Fibrocytes and fibrosis. Q J Med. 2012; 105: 505-508Google Scholar, Peng and Herzog, 2012Peng H. Herzog E.L. Fibrocytes: emerging effector cells in chronic inflammation.Curr Opin Pharmacol. 2012; 12: 491-496Crossref PubMed Scopus (56) Google Scholar). Fibrocytes can also respond to other stimuli, such as TGF-β, viral infections, and toll-like receptor ligands, expressing class II major histocompatibility complex and costimulatory molecules, exhibiting a strong antigen-presenting capability (Bucala, 2012Bucala R. Review series—inflammation & fibrosis.Fibrocytes and fibrosis. Q J Med. 2012; 105: 505-508Google Scholar). Taken together, these observations suggest that fibrocytes are relevant in both early events of inflammation and later remodeling. This combination of proinflammatory and profibrotic signatures is commonly observed in several chronic conditions including skin fibrotic disorders and autoimmune diseases. We still have unanswered questions that might increase the already known broad range of effects of TSLP. It is essential to understand TSLP/SDF-1 signaling in greater detail and whether it is dependent on TGF-β. Most importantly, it would be useful to determine whether this novel axis is organ specific, because TSLP, SDF-1, and fibrocytes may have distinct roles in lung fibrosis. Answers to these questions may open new avenues of research with the goal of finding desperately needed antifibrotic therapies. The author states no conflict of interest. TSLP Is a Potential Initiator of Collagen Synthesis and an Activator of CXCR4/SDF-1 Axis in Keloid PathogenesisJournal of Investigative DermatologyVol. 136Issue 2PreviewRecently, thymic stromal lymphopoietin (TSLP), which is well studied in allergic diseases, has been reported in fibrotic diseases, including idiopathic pulmonary fibrosis and atopic dermatitis fibrosis. However, the role of TSLP in keloid is obscure. In this study, we assessed the expression of TSLP in keloid tissue and investigated the possible role of TSLP in keloid pathogenesis. We observed that TSLP expression was increased in keloid tissue compared to normal tissue. Furthermore, TSLP treatment induced increased collagen I and collagen III expression in fibroblasts via transforming growth factor-β; however, there was higher expression in keloid fibroblasts compared to normal fibroblasts. Full-Text PDF Open Archive