Lymphotoxin beta receptor signaling directly controls airway smooth muscle deregulation and asthmatic lung dysfunction

ABSTRACT

Background

Dysregulation of airway smooth muscle cells (ASM) is central to the severity of asthma. Which molecules dominantly control ASM in asthmatics is unclear. High levels of the cytokine LIGHT (TNFSF14) have been linked to asthma severity and lower baseline FEV₁ %predicted, implying signals through its receptors might directly control ASM dysfunction.

Objective

To determine whether signaling via LTβR or HVEM from LIGHT dominantly drives ASM hyperreactivity induced by allergen.

Methods

Conditional knockout mice deficient for LTβR or HVEM in smooth muscle cells were used to determine their role in ASM deregulation and airway hyperresponsiveness (AHR) in vivo. Human ASM were used to study signals induced by LTβR.

Results

LTβR was strongly expressed in ASM from normal and asthmatic subjects compared to several other receptors implicated in smooth muscle deregulation. Correspondingly, conditional deletion of LTβR only in smooth muscle cells in smMHC^CreLTβR^fl/fl mice minimized changes in their numbers and mass, and AHR, induced by house dust mite allergen in a model of severe asthma. Intratracheal LIGHT administration independently induced ASM hypertrophy and AHR in vivo dependent on direct LTβR signals to ASM. LIGHT promoted contractility, hypertrophy, and hyperplasia of human ASM in vitro. Distinguishing LTβR from the receptors for IL-13, TNF, and IL-17 that have also been implicated in smooth muscle dysregulation, LIGHT promoted NIK-dependent non-canonical NF-κB in ASM in vitro, leading to sustained accumulation of F-actin, phosphorylation of myosin light chain kinase, and contractile activity.

Conclusion

LTβR signals directly and dominantly drive airway smooth muscle hyperresponsiveness relevant for pathogenesis of airway remodeling in severe asthma.