title: Extra domain A-positive fibronectin-positive feedback loops and their association with cutaneous inflammatory disease.
abstract: Cutaneous inflammation can show Th1 or Th2 predominance, but the precise mechanisms by which such selectivity is determined are unknown. A recent study has demonstrated that Th1 cells, but not Th2 cells, produce an endogenous ligand for Toll-like receptor (TLR) 4, namely extradomain A+ fibronectin containing extra type III domain A (FnEDA+). As TLR4 stimulation leads to production of proinflammatory cytokines that recruit (via altered endothelial adhesion molecule expression and chemokine production) more Th1/Th17 cells, a positive feedback mechanism for Th1/Th17 inflammation exists. We propose that FnEDA+ positive feedback loops are a potential driver of Th1/Th17 inflammation. Conversely, the inflammatory EDA+ fibronectin loop is negatively regulated in atopic dermatitis, Th2 cytokines actively suppress TLR4 expression of Th1 cytokines, and recruited Th2 cells do not produce FnEDA+. In psoriasis, there are multiple FnEDA+ loops, comprising inflammatory, keratinocyte, and autoimmune loops. In allergic contact dermatitis, a single inflammatory loop operates. In atopic dermatitis, the FnEDA+ loop is actively suppressed by Th2 cytokines, and recruited Th2 cells do not "feedback" FnEDA+. We review endogenous ligands for TLR in relation to inflammatory disease, FnEDA+ function, and the potential role for FnEDA+ in psoriasis, allergic contact dermatitis, and atopic dermatitis.
authors.affiliation: Department of Cutaneous Allergy, St John's Institute of Dermatology, St Thomas' Hospital, SE1 7EH London, UK. john.mcfadden@kcl.ac.uk
authors.forename: John P
authors.initials: JP
authors.lastname: McFadden
authors.forename: David A
authors.initials: DA
authors.lastname: Basketter
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Dearman
authors.forename: Ian R
authors.initials: IR
authors.lastname: Kimber
mesh_terms: D003872:Dermatitis / Q000276:immunology*; D017449:Dermatitis, Allergic Contact / Q000276:immunology; D003876:Dermatitis, Atopic / Q000276:immunology; D005353:Fibronectins / Q000276:immunology*; D006801:Humans; D011565:Psoriasis / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D005353:Fibronectins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4