LIGHT, the Tumor Necrosis Superfamily Protein 14 (TNFSF14), Controls Lung and Skin Fibrosis.

Abstract

Abstract Lung and skin fibrosis are characterized by excessive accumulation of collagen and α-smooth muscle actin in these organs. The key molecules that promote these phenotypes are of clinical interest. Thymic stromal lymphopoietin (TSLP) and Periostin (Pstn) have been found at high levels in patients with Asthma, Idiopathic Pulmonary Fibrosis, and Atopic Dermatitis. TSLP has been proposed as a primary driver of lung fibrotic disease, while Pstn was found to be an important mediator of Asthma and Systemic Sclerosis. We asked whether LIGHT (aka TNFSF14) controls TSLP and Pstn production to initiate fibrosis. Genetic deletion of LIGHT abolished TSLP and Pstn expression driven by bleomycin used to induce fibrosis, accompanied by near-complete absence of accumulation of lung and skin collagen and α-smooth muscle actin. Furthermore, recombinant LIGHT administered in vivo induced lung and skin expression of both TSLP and Pstn in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a TSLP-dependent manner. Blockade of LIGHT binding to either of its receptors, herpes virus entry mediator and lymphotoxin beta receptor, inhibited clinical symptoms of lung and skin fibrosis, and correspondingly both receptors were found on human epithelial cells and fibroblasts, primary sources of TSLP and Pstn respectively. Moreover, LIGHT induced TSLP directly in human bronchial epithelial cells and keratinocytes and synergized with IL-13 and TGF-β in vivo to promote TSLP expression and drive fibrosis. These results show that LIGHT is a profibrogenic cytokine that may be a key driver of TSLP and Pstn production during the initiation and development of fibrotic diseases in the lung and skin.