Psoriasis and extra domain A fibronectin loops.
We have previously postulated that as well as T-helper (Th) 1 and Th17 cells, the transforming growth factor (TGF)-beta/fibronectin (FN)/alpha5beta1 pathway is central to psoriasis pathogenesis. EDA+ FN refers to an alternatively spliced isoform of FN with an additional domain known as extra domain A. EDA+ FN has two important properties pertinent to psoriasis lesions: it stimulates keratinocyte hyperproliferation, and, through stimulation of Toll-like receptor (TLR) 4, stimulates production of proinflammatory cytokines. EDA+ FN production induced by TGF-beta stimulation can be maintained in psoriasis lesions via two main feedback loops. Firstly, EDA+ FN stimulates proliferation of keratinocytes, which, in an autocrine fashion, will release more EDA+ FN. Secondly, EDA+ FN stimulates TLR4 expressed by antigen-presenting cells resulting in the production of proinflammatory cytokines such as tumour necrosis factor-alpha, interleukin (IL)-1, IL-6 and IL-12. The resultant promotion of cutaneous inflammation results in the recruitment of Th1 cells, which also produce EDA+ FN. We propose that these 'FN loops' contribute to the maintenance and progression of psoriatic lesions. Finally, although the association between psoriasis and heart/thrombotic disease remains unclear one plausible link may be the promotion of atherosclerosis and thrombotic heart disease by EDA+ FN.
McFadden
J P
JP
Department of Cutaneous Allergy, St John's Institute of Dermatology, St Thomas' Hospital, London SE1 7EH, UK. john.mcfadden@kcl.ac.uk
Baker
B S
BS
Powles
A V
AV
Fry
L
L
D049109:Cell Proliferation; D002478:Cells, Cultured; D005353:Fibronectins / Q000276:immunology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D020033:Protein Isoforms / Q000276:immunology; D011565:Psoriasis / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
D005353:Fibronectins; D020033:Protein Isoforms; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta