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Fibrosis in systemic sclerosis: common and unique pathobiology.

Bhattacharyya S, Wei J, Tourtellotte WG, Hinchcliff M, Gottardi CG, Varga J - Fibrogenesis Tissue Repair (2012)

Bottom Line: Fibrosis in systemic sclerosis (SSc), a complex polygenic disease associated with autoimmunity and proliferative/obliterative vasculopathy, shares pathobiologic features in common with other fibrosing illnesses, but also has distinguishing characteristics.On the other hand, the roles of endothelial-mesenchymal differentiation and bone marrow-derived fibrocytes remain to be established.Fibrotic responses are modulated by transcriptional activators and cofactors, epigenetic factors, and microRNAs that can amplify or inhibit ligand-induced signaling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Medicine and Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

ABSTRACT
Fibrosis in systemic sclerosis (SSc), a complex polygenic disease associated with autoimmunity and proliferative/obliterative vasculopathy, shares pathobiologic features in common with other fibrosing illnesses, but also has distinguishing characteristics. Fibroblast activation induced by transforming growth factor-β (TGF-β), Wnts and innate immune receptors, along with oxidative stress and reactive oxygen species (ROS) are implicated in pathogenesis. On the other hand, the roles of endothelial-mesenchymal differentiation and bone marrow-derived fibrocytes remain to be established. Fibrotic responses are modulated by transcriptional activators and cofactors, epigenetic factors, and microRNAs that can amplify or inhibit ligand-induced signaling. The nuclear orphan receptor PPAR-γ appears to be important in governing the duration and intensity of fibroblast activation and mesenchymal progenitor cell differentiation, and defects in PPAR-γ expression or function in SSc may underlie the uncontrolled progression of fibrosis. Identifying the perturbations in signaling pathways and cellular differentiation programs responsible for tissue damage and fibrosis in SSc allows their selective targeting using novel compounds, or by innovative uses of already-approved drugs (drug repurposing).

No MeSH data available.


Related in: MedlinePlus

Vicious cycle of FIBROSIS. Innate immune signaling alters self-limited repair into sustained fibrogenic process. Following injury, fibroblasts undergo a regulated activation. Once repair has been accomplished, tissue regeneration is complete. Prolonged injury leads to damage, causes activation of toll like receptors and sustained fibroblast activation culminating in excessive fibrogenesis.
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Figure 1: Vicious cycle of FIBROSIS. Innate immune signaling alters self-limited repair into sustained fibrogenic process. Following injury, fibroblasts undergo a regulated activation. Once repair has been accomplished, tissue regeneration is complete. Prolonged injury leads to damage, causes activation of toll like receptors and sustained fibroblast activation culminating in excessive fibrogenesis.

Mentions: Innate immune recognition signaling via toll-like receptors (TLRs) appears to play an important role in the persistent fibrotic response in SSc. The ability to recognize pathogen-associated molecular patterns via pattern recognition receptors (PRRs) is a critical aspect of the host ability to respond to foreign microorganisms [6]. We have demonstrated that TLR3 and TLR4 are expressed in normal fibroblasts and transduce signals from lipopolysaccharide (LPS) as well as endogenous TLR ligands, the so-called damage-associated molecular pattern (DAMPs) such as polyinosinic:polycytidylic acid and matrix components such as hyaluronic acid, and fibronectin-EDA (Fn-EDA) [7,8]. In the liver, TLR4 activated by LPS plays a critical role in fibrosis, with suppression of BAMBI and sensitization to TGF-β as the underlying mechanisms [9]. We speculate that in SSc tissue injury, exacerbated by hypoxia and accumulation of reactive oxygen species (ROS), up-regulate fibroblast TLR4 expression and/or activity on mesenchymal stromal cells, contributing to TLR-mediated amplification of TGF-β signaling. Moreover, oxidative damage and tissue remodeling generating DAMPs such as low molecular weight hyaluronan degradation products, Fn-EDA, Tenascin C, and biglycan; cellular stress proteins such as HMGB1 and Hsp60; and nucleic acids and immune complexes, each of which might activate fibroblasts via TLRs engagement. In this way, the accumulation of tissue damage-associated endogenous TLR ligands serve as a danger signals that perpetuate fibroblasts activation. We speculate that DAMP-induced TLR signaling might serve as the critical "switch" that, when turned on, converts a self-limited tissue repair process into one of persistent and unchecked fibroblasts activation resulting in progressive fibrosis in SSc. This concept is illustrated in Figure 1.


Fibrosis in systemic sclerosis: common and unique pathobiology.

Bhattacharyya S, Wei J, Tourtellotte WG, Hinchcliff M, Gottardi CG, Varga J - Fibrogenesis Tissue Repair (2012)

Vicious cycle of FIBROSIS. Innate immune signaling alters self-limited repair into sustained fibrogenic process. Following injury, fibroblasts undergo a regulated activation. Once repair has been accomplished, tissue regeneration is complete. Prolonged injury leads to damage, causes activation of toll like receptors and sustained fibroblast activation culminating in excessive fibrogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368774&req=5

Figure 1: Vicious cycle of FIBROSIS. Innate immune signaling alters self-limited repair into sustained fibrogenic process. Following injury, fibroblasts undergo a regulated activation. Once repair has been accomplished, tissue regeneration is complete. Prolonged injury leads to damage, causes activation of toll like receptors and sustained fibroblast activation culminating in excessive fibrogenesis.
Mentions: Innate immune recognition signaling via toll-like receptors (TLRs) appears to play an important role in the persistent fibrotic response in SSc. The ability to recognize pathogen-associated molecular patterns via pattern recognition receptors (PRRs) is a critical aspect of the host ability to respond to foreign microorganisms [6]. We have demonstrated that TLR3 and TLR4 are expressed in normal fibroblasts and transduce signals from lipopolysaccharide (LPS) as well as endogenous TLR ligands, the so-called damage-associated molecular pattern (DAMPs) such as polyinosinic:polycytidylic acid and matrix components such as hyaluronic acid, and fibronectin-EDA (Fn-EDA) [7,8]. In the liver, TLR4 activated by LPS plays a critical role in fibrosis, with suppression of BAMBI and sensitization to TGF-β as the underlying mechanisms [9]. We speculate that in SSc tissue injury, exacerbated by hypoxia and accumulation of reactive oxygen species (ROS), up-regulate fibroblast TLR4 expression and/or activity on mesenchymal stromal cells, contributing to TLR-mediated amplification of TGF-β signaling. Moreover, oxidative damage and tissue remodeling generating DAMPs such as low molecular weight hyaluronan degradation products, Fn-EDA, Tenascin C, and biglycan; cellular stress proteins such as HMGB1 and Hsp60; and nucleic acids and immune complexes, each of which might activate fibroblasts via TLRs engagement. In this way, the accumulation of tissue damage-associated endogenous TLR ligands serve as a danger signals that perpetuate fibroblasts activation. We speculate that DAMP-induced TLR signaling might serve as the critical "switch" that, when turned on, converts a self-limited tissue repair process into one of persistent and unchecked fibroblasts activation resulting in progressive fibrosis in SSc. This concept is illustrated in Figure 1.

Bottom Line: Fibrosis in systemic sclerosis (SSc), a complex polygenic disease associated with autoimmunity and proliferative/obliterative vasculopathy, shares pathobiologic features in common with other fibrosing illnesses, but also has distinguishing characteristics.On the other hand, the roles of endothelial-mesenchymal differentiation and bone marrow-derived fibrocytes remain to be established.Fibrotic responses are modulated by transcriptional activators and cofactors, epigenetic factors, and microRNAs that can amplify or inhibit ligand-induced signaling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Medicine and Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

ABSTRACT
Fibrosis in systemic sclerosis (SSc), a complex polygenic disease associated with autoimmunity and proliferative/obliterative vasculopathy, shares pathobiologic features in common with other fibrosing illnesses, but also has distinguishing characteristics. Fibroblast activation induced by transforming growth factor-β (TGF-β), Wnts and innate immune receptors, along with oxidative stress and reactive oxygen species (ROS) are implicated in pathogenesis. On the other hand, the roles of endothelial-mesenchymal differentiation and bone marrow-derived fibrocytes remain to be established. Fibrotic responses are modulated by transcriptional activators and cofactors, epigenetic factors, and microRNAs that can amplify or inhibit ligand-induced signaling. The nuclear orphan receptor PPAR-γ appears to be important in governing the duration and intensity of fibroblast activation and mesenchymal progenitor cell differentiation, and defects in PPAR-γ expression or function in SSc may underlie the uncontrolled progression of fibrosis. Identifying the perturbations in signaling pathways and cellular differentiation programs responsible for tissue damage and fibrosis in SSc allows their selective targeting using novel compounds, or by innovative uses of already-approved drugs (drug repurposing).

No MeSH data available.


Related in: MedlinePlus