Fibronectin feedback loops and their relationship with inflammatory skin diseases (48.11)

Abstract

Abstract There are several forms of the extracellular matrix protein fibronectin (Fn), such as the alternatively spliced embryonic form that bears an Extra Domain A (FnEDA). This molecule is produced by both T helper (Th) 1 cells and hyperproliferating keratinocytes and binds toll-like receptor (TLR) 4 and induces psoriatic keratinocyte (PK) proliferation. We hypothesise that there are discrete FnEDA feedback loops that impact directly or indirectly on the behaviors of various skin cells and thereby influence skin disease processes. TLR4 stimulation leads to cytokine, chemokine and adhesion molecule expression resulting in Th1/Th17 cell recruitment. Production of FnEDA by recruited Th1 cells will lead to an “inflammatory” FnEDA positive feedback loop. Proliferating PK also release FnEDA in an autocrine fashion (“keratinocyte” loop) and hyperproliferative keratin, a potential autoantigen. An autoimmune reaction would lead to Th1/Th17 cell recruitment with further FnEDA production (“autoimmune” loop). In contrast, in atopic dermatitis (AD) IL-4, IL-13 and vasoactive intestinal peptide down regulate TLR4 and Th2 cells do not produce FnEDA. Therefore, the inflammatory FnEDA loop appears to be actively suppressed in AD, allowing for Th2 dominance. Thus, the inflammatory FnEDA loop is central to Th1/Th17 driven skin inflammatory diseases such as allergic contact dermatitis, whereas there is active down-regulation of this loop in AD and all three FnEDA loops feature in psoriasis.