Stimulating Receptor Active in Immune System Eases Fibrosis in Mouse Model
Stimulating the aryl hydrocarbon receptor (AhR), found across the immune system, via a naturally produced chemical protected mice from induced pulmonary fibrosis (PF) and increased their survival, a study showed.
These findings support further research to determine if AhR might be a useful therapeutic target for PF.
The study, “Aryl hydrocarbon receptor signals attenuate lung fibrosis in the bleomycin-induced mouse model for pulmonary fibrosis through increase of regulatory T cells,” was published in the journal Arthritis Research & Therapy.
PF is an interstitial lung disease (ILD) characterized by the presence of scarred tissue in the lungs, thought to be caused by both genetic factors and environmental triggers, such as occupational and environmental exposure to substances that can cause irritation.
AhR is a molecule that appears to directly connect environmental factors with the immune system by binding to foreign (xenobiotic) substances. Recent research has identified another role for AhR: it binds to a variety of biochemicals, such as derivatives of the amino acid tryptophan.
AhR is widely expressed in the immune system, and its activation can modulate immune responses. Treating inflammatory animal models with chemicals that bind and stimulate AhR has been shown to lessen disease processes.
These findings prompted a team, led by researchers at Keio University School of Medicine in Japan, to wonder if modulating AhR signals would affect the process of lung fibrosis and other disease-related immunological features.
To test this idea, researchers used the bleomycin (BLM)-induced lung fibrosis mouse model.
To trigger fibrosis, BLM was administered to mice. On the same day, the next day, and two days later, some of these mice were given an injection of the chemical 5,11-dihydro-indolo[3,2-b]carbazole-6-carboxaldehyde (FICZ) — a non-toxic, natural chemical that binds tightly to AhR, thus stimulating its activity.
Results showed that while BLM induced marked lung tissue fibrosis in the animals, those mice treated with FICZ had less fibrosis.
An assessment using the Ashcroft score, which measures the amount of fibrotic tissue, showed a significantly higher score in BLM mice (left as control group) compared to those treated with FICZ. Soluble collagen deposition was also significantly lower in FICZ-treated mice.
Mice treated with FICZ also had significantly better survival than control mice over the experiment’s three weeks.
To investigate the mechanism underlying the diminished fibrosis in the lungs of FICZ-treated mice, the team analyzed populations of different immune cells.
No difference was found in most immune cell populations between these groups (FICZ-treated and control mice), but one cell type — known as T regulatory cells (Tregs) — was significantly higher. Tregs are immunosuppressive cells, working to modulate the immune system to prevent autoimmune disease.
FICZ-treated mice also had significantly fewer pro-inflammatory T-cells in their lungs compared to control mice.
“This study showed that FICZ, a natural AhR ligand, alleviated lung fibrosis and improved survival in a BLM-induced mouse model,” the researchers wrote, adding that “stimulation of AhR signals attenuated lung fibrosis by increasing Tregs and suppressing inflammatory T-cell subsets.”
“Taken together, our results indicate that the immunological changes induced by AhR stimulation may contribute to attenuating lung fibrosis,” the team concluded.