Tnfsf14 (Light) Induces Airway Smooth Muscle Contraction

Asthma is a chronic inflammatory disorder characterized by reversible airway obstruction and airway hyperresponsiveness (AHR). The precise mechanism responsible for AHR is not known but it may involve excess mucus production and alterations in airway smooth muscle cell (SMC) activity. SMC from asthmatic patients are thought to generate more force and contract to a greater extent to allergens or certain inflammatory stimuli, but which inflammatory stimuli in asthmatics drive contraction is still not clear. Previously, we showed that the tumor necrosis factor superfamily member LIGHT (TNFSF14) promotes airway remodeling and AHR in mouse models of chronic asthma, despite having little effect on airway eosinophilia. Exogenous administration of rLIGHT to the mouse airways also induced smooth muscle hyperplasia. We found that LTβR and HVEM, the receptors for LIGHT, are expressed on both human and mouse SMC from the lungs, with LTbR primarily expressed on human cells, suggesting a direct effect of this T cell-derived cytokine. From studies in vitro with primary human SMC, we found that rLIGHT administration induced contraction of SMC in collagen-gels in 3D structures, and migration of SMC in monolayers. rLIGHT induced both actin polymerization and phosphorylation of myosin light chain which leads to actomyosin formation to induce contraction. rLIGHT promoted both canonical and non-canonical NF-kB in airway SMC, and these signals activated the small GTPase Rac1 and P21-Activated Kinase 1 (PAK1) which are involved in actin rearrangement and myosin light chain kinase activity. These results reveal direct evidence that LIGHT can drive SMC contraction and may directly regulate airway hyperresponsiveness relevant to asthma pathogenesis.