The TNF Superfamily member LIGHT (TNFSF14) has recently emerged as a potential target for therapeutic interventions aiming to halt tissue
fibrosis. In this perspective, we discuss how LIGHT may influence the inflammatory and remodeling steps that characterize
fibrosis, relevant for many human diseases presenting with
scarring such as
asthma,
idiopathic pulmonary fibrosis,
systemic sclerosis, and
atopic dermatitis. LIGHT acts through two receptors in the
TNF receptor superfamily, HVEM (TNFRSF14) and LTβR (TNFRSF3), which are broadly expressed on hematopoietic and non-hematopoietic cells. LIGHT can regulate infiltrating T cells, macrophages, and eosinophils, controlling their trafficking or retention in the inflamed tissue, their proliferation, and their ability to produce
cytokines that amplify fibrotic processes. More interestingly, LIGHT can act on structural cells, namely epithelial cells, fibroblasts, smooth muscle cells, adipocytes, and endothelial cells. By signaling through either HVEM or LTβR expressed on these cells, LIGHT can contribute to their proliferation and expression of
chemokines,
growth factors, and
metalloproteinases. This will lead to
hyperplasia of epithelial cells, fibroblasts, and smooth muscle cells, deposition of
extracellular matrix proteins, vascular damage, and further immune alterations that in concert constitute
fibrosis. Because of its early expression by T cells, LIGHT may be an initiator of fibrotic diseases, but other sources in the immune system could also signify a role for LIGHT in maintaining or perpetuating fibrotic activity. LIGHT may then be an attractive prognostic marker as well as an appealing target for
fibrosis therapies relevant to humans.