Blocking the TNF Superfamily member LIGHT to control lung and skin fibrosis

Abstract

Abstract Anti-inflammatory drugs have so far failed to reduce fibrosis and tissue remodeling in the clinic. Alternatively, 5 TNF inhibitors have been FDA approved to treat different inflammatory diseases and are safe to administer to patients. In human, LIGHT and its receptors have been linked to numerous autoimmune and inflammatory diseases with fibrotic components. We show that blocking LIGHT signaling in isolation is efficient in reducing fibrosis in the skin and lung of mice induced with bleomycin to mimic human Systemic Sclerosis and Idiopathic pulmonary fibrosis, as well as in 2 severe allergen-driven models of asthma and atopic dermatitis. Neutralizing LIGHT signaling through its receptors by genetic deletion or antibody blocking, dramatically decreased collagen and smooth muscle deposition in the lungs and skins. Moreover the specific deletion of LIGHT-receptor HVEM on keratinocytes or the therapeutic blocking of LIGHT-HVEM interaction post-disease onset, abrogated skin fibrosis induced by house dust mite in a model of atopic dermatitis. LIGHT seems to play a central role in lung and skin fibrosis since it can control the expression of major pro-fibrotic factors such as TSLP, IL-13, TGF-b and Periostin. Also LIGHT alone can induce a fibro-proliferative disorder that mimics human SSc, in the lung and skin when administered alone, by increasing the accumulation of both fibers collagen and smooth muscle actin. Lastly we observed an upregulation of LIGHT and its receptors in lung biopsies of patients suffering from asthma, scleroderma and idiopathic pulmonary fibrosis. The relevance of this work to fibrosis therapies associated with asthma, atopic dermatitis, scleroderma and idiopathic pulmonary fibrosis are tremendous.