Study results suggest blocking TNF family protein may halt lung remodeling.
Researchers claim the TNF protein family member LIGHT may represent a new target for halting the process of airway remodeling that leads to decreased lung function in asthma patients. A team headed by scientists at La Jolla Institute for Allergy and Immunology has shown that blocking LIGHT’s interaction with its two receptors, HVEM and LTβR, reduces lung fibrosis, smooth muscle hyperplasia, and airway hyperresponsiveness in mouse models of house dust mite-induced chronic asthma.
The studies, led by Michael Croft, Ph.D., found that genetic and antibody-mediated blockade of LIGHT prevents remodeling and decreased lung function as a result of allergen exposure, without altering the influx of immune cells into the lung. The team reports its findings in Nature Medicine in a paper titled, “The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling.”
Patients with severe asthma exhibit chronic unresolved inflammation in the lungs leading to remodeling of the airways, fibrosis, and decreased lung function, the authors explain. Unfortunately, despite controlling airway inflammation, current therapies used to treat asthma have little effect on this remodeling process. Dr. Croft’s team has now found that this mechanism is triggered by the TNF family member LIGHT expressed on activated immune cells after exposure to allergens from house dust mites.
Previous studies, including research at Dr. Croft’s laboratory, have implicated other TNF superfamily members including OX40 ligand and TNF itself as key mediators in asthmatic inflammation. A recent study in addition found that LIGHT levels in the sputum of asthma patients correlated with decreased lung function. This growing collection of evidence led the La Jolla team to hypothesize that LIGHT might be directly involved in driving aspects of lung inflammation or airway remodeling.
The researchers used antibodies to block LIGHT from interacting with its two receptors LTβR and HVEM in a mouse model of house dust mite-induced chronic asthma and in a second mouse model in which ovalbumin was used as the antigen for sensitization and chronic repetitive airway challenges.
They found that preventing LIGHT interactions suppressed the expression of lung transforming growth factor-β (TGF-β) and interleukin-13 (IL-13), which are both cytokines implicated in lung remodeling in humans. Conversely, exogenous administration of LIGHT to the airways of LIGHT-deficient mice induced fibrosis and smooth muscle hyperplasia.
Importantly, LIGHT-deficient mice had reduced percentages and absolute numbers of lung macrophages after chronic challenge with their relevant antigens. Lung macrophages express one of LIGHT’s ligands, LTβR, and the researchers found that when sensitized, antigen-challenged mice were given an agonist antibody to LTβR13 the animals not only demonstrated a marked induction of fibrosis above the level found in acutely challenged mice, but double the number of relevant macrophages.
The collected findings strongly suggest that “LIGHT regulates macrophage accumulation in the lung and directly or indirectly regulates the number of TGF-β–producing cells,” the authors claim. “Collectively, these data indicate that LIGHT is required in models of chronic asthma for maximal expression of two of the primary cytokines thought to promote airway remodelling, and that LIGHT-LTβR or LIGHT-HVEM interactions promote remodeling activities of lung macrophages and lung eosinophils, two of the cell types associated with chronic asthma and remodelling in humans,” they add. “Notably, our data presents a new role for this molecule in lung remodeling and fibrotic disease and suggests that LIGHT may be a relevant target for suppressing fibrosis and smooth muscle hyperplasia.”