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.