An inflammatory molecule called LIGHT, appears to be the explanation for life-threatening airway damage in patients with severe asthma. In keeping with the brand new research from scientists at La Jolla Institute for Immunology (LJI), therapeutics to stop LIGHT (which is said to tumor necrosis factor) could reverse airway and lung damage in patients-;and potentially offer a long-term treatment for asthma.

It is a very, very significant finding. This research gives us a greater understanding of the potential of therapeutic targeting of LIGHT and what we would do to alleviate among the symptoms and among the inflammatory features seen in patients who’ve severe asthma.”

Michael Croft, Ph.D.,  LJI professor, senior creator of the brand new study and member of the LJI Center for Autoimmunity and Inflammation

This research was published recently within the Journal of Allergy and Clinical Immunology. The study included experiments with each mouse and human tissues and was spearheaded by LJI Instructor Haruka Miki, M.D., Ph.D.

Croft’s team has studied LIGHT for greater than a decade. The LIGHT protein is a variety of inflammatory “cytokine” produced by the immune system’s T cells. T cells normally fight disease, but in asthma, T cells overreact to environmental triggers and flood the airways with LIGHT and other inflammatory cytokines. Researchers have developed therapies to dam the activity of among the other harmful cytokines made by T cells, but these therapies aren’t effective for a lot of with severe asthma.

LIGHT might be found elevated within the sputum of asthmatic patients with severe disease, and Croft’s previous work showed that LIGHT is crucial in a process called tissue “remodeling,” where the lungs and airways grow thicker following an asthma attack. These thicker airways can leave an individual with long-term respiration problems.

“Current treatments for asthma are mainly to suppress symptoms and subdue allergic inflammation. No treatment has been developed to fundamentally cure asthma,” says Miki. “Even when inflammation is suppressed by current treatments, underlying airway hyperresponsiveness and airway tissue changes (airway remodeling) often remain, especially in severe asthma.”

Regardless that they knew LIGHT was involved on this remodeling, the researchers didn’t know whether LIGHT directly affects the graceful muscle tissue that lines the foremost airways of the lungs. These cells increase in number and size in moderate and severe asthmatics, which is considered a primary explanation for lack of lung function.

Their investigation showed that one in all the 2 receptors for LIGHT, named LTβR, was strongly expressed on airway smooth muscle cells. By then “knocking out” the genes for one receptor or the opposite in mice, Miki was in a position to show that LIGHT’s binding with LTβR is what triggers tissue remodeling within the airway smooth muscles. The researchers further confirmed this finding using bronchial smooth muscle tissue from human samples.

“When those cells within the lungs cannot express LTβR, then essentially the entire hallmarks of the graceful muscle response related to severe asthma are either gone or they’re highly limited,” says Croft.

In fact, LIGHT is not the only cytokine in the combo during an asthma attack, but the brand new study suggests that LIGHT packs the most important punch. By acting directly on airway smooth muscle cells, LIGHT coordinates the reworking process. Without LIGHT and LTβR activity, the opposite cytokines cannot pick up the slack. The truth is, the brand new study is the primary to point out that the deletion of a single receptor or absence of a single cytokine can limit airway smooth muscle tissue remodeling.

“Unlike other inflammatory cytokines, LIGHT induces a delayed and chronic signal via its receptor, LTβR, which could also be liable for the sustained increase in contractility and mass in airway smooth muscle,” says Miki.

“It is a very striking and significant result that essentially separates LIGHT from any of the opposite inflammatory cytokines which have been implicated in the method in severe asthmatics,” adds Croft.

Straight away, pharmaceutical company and LJI research partner Kiowa Kirin is advancing a possible therapeutic based on Croft’s finding. For Croft, the study is the long-awaited conclusion to years of research. “I believe it completes the circle that we began a few years ago in first linking LIGHT to lung inflammation,” he says.

Source:

La Jolla Institute for Immunology

Journal reference:

Miki, H., et al. (2022) LTβR Signaling Directly Controls Airway Smooth Muscle Deregulation and Asthmatic Lung Dysfunction. Journal of Allergy and Clinical Immunology. doi.org/10.1016/j.jaci.2022.11.016.