title: Emerging roles of innate immune signaling and toll-like receptors in fibrosis and systemic sclerosis.
abstract: Pathological fibrosis is a distinguishing hallmark of systemic sclerosis (SSc) as well as a number of more common conditions. Fibrosis is a complex and dynamic process associated with immune dysregulation, vasculopathy, and uncontrolled extracellular matrix production leading to intractable scar formation in the skin and internal organs. Persistent or recurrent chemical, infectious, mechanical, or autoimmune injury in genetically predisposed individuals causes sustained fibroblasts activation. Innate immune signaling via toll-like receptors (TLRs) is increasingly recognized as a key player driving the persistent fibrotic response in SSc. In particular, expression of TLR4 as well as its endogenous ligands are elevated in lesional tissue from patients with SSc. Ligand-induced TLR4 activation elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation. Furthermore, TLR4 appears to sensitize fibroblasts to the profibrotic stimulatory effect of transforming growth factor-β. This review highlights recent advances and emerging paradigms for understanding the regulation, complex functional roles, and therapeutic potential of TLRs in SSc pathogenesis.
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E. Huron St., Chicago, IL, 60611, USA, s-bhattacharyya@northwestern.edu.
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D005347:Fibroblasts / Q000276:immunology; D005355:Fibrosis; D006801:Humans; D007113:Immunity, Innate; D012595:Scleroderma, Systemic / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors