Aryl hydrocarbon receptor signals attenuate lung fibrosis in the bleomycin-induced mouse model for pulmonary fibrosis through increase of regulatory T cells

Hiroshi Takei,Hidekata Yasuoka,Keiko Yoshimoto,Tsutomu Takeuchi

doi:10.1186/s13075-020-2112-7

Abstract

BackgroundInterstitial lung disease (ILD) is a serious complication of connective tissue diseases (CTDs). Although immune dysregulation triggered by genetic and environmental factors is thought to provoke inflammation and subsequent fibrosis, precise mechanisms of these processes remain unclear. Recent reports suggest that activation of aryl hydrocarbon receptor (AhR) signals by various ligands such as tryptophan derivatives can induce hyper-immune responses and are involved in autoimmunity. We investigated the effects of AhR signals on the process of lung fibrosis and changes in immunological features using a bleomycin (BLM)-induced lung fibrosis mouse model.MethodsBLM was administered intratracheally to C57BL/6JJcl mice and either 5,11-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (FICZ), a natural AhR ligand, or vehicle was subsequently injected intraperitoneally on day 0, 1, and 2 from BLM administration. Mice were sacrificed at week 3, and lung fibrosis was quantified by the histological changes using the Ashcroft score and deposition of soluble collagen levels in the lung using Sircol assay. The population of immune cells infiltrated into the lungs was analyzed using flow cytometry.ResultsBoth the Ashcroft score and soluble collagen level in FICZ-treated mice were significantly lower than those in the vehicle group. Moreover, the survival rate of FICZ-treated mice was significantly higher than that of control mice during the 3 weeks after treatment. Interestingly, flow cytometric analysis revealed that the number of CD4+Foxp3+ regulatory T cells (Tregs) was significantly increased and CD4+IFNγ+ and γδ+IL-17A+ T cells were decreased in the lungs of FICZ-treated mice, while the total number of T, B, and NK cells were unaffected by FICZ treatment.ConclusionsOur findings suggest that stimulation of AhR signals attenuated lung fibrosis by increasing Tregs and suppressing inflammatory T cell subsets in a BLM-induced fibrosis model. AhR signaling pathways may therefore be useful therapeutic targets for connective tissue disease-associated ILD.

Highlights

Interstitial lung disease (ILD) is a frequent and serious complication in patients with connective tissue diseases (CTDs) and is associated with significant morbidity and mortality [1, 2]
Recent reports have revealed that the aryl hydrocarbon receptor (AhR) is widely expressed in the immune system and that activation of AhR by its ligands has modulatory effects on the immune system, including balancing the differentiation of regulatory T cells (Tregs) and IL-17-producing helper T cells (Th17 cells), which may be associated with autoimmunity [8, 9, 11, 12]
Our findings suggest that administration of FICZ to BLM-induced pulmonary fibrosis model mice increased the number of CD4+Foxp3+ Regulatory T cells (Tregs) and reduced the number of CD4+IFNγ+ and γδ+IL-17A+ T cell populations in the lungs and contributed to improve or attenuate lung inflammation induced by BLM

Summary

Introduction

Interstitial lung disease (ILD) is a frequent and serious complication in patients with connective tissue diseases (CTDs) and is associated with significant morbidity and mortality [1, 2]. The aryl hydrocarbon receptor (AhR) is a unique molecule with an emerging role that appears to directly connect environmental factors with the immune system [8, 9]. We hypothesized that AhR signaling may be involved in the process of lung fibrosis via its modulatory effects on the immune system. Immune dysregulation triggered by genetic and environmental factors is thought to provoke inflammation and subsequent fibrosis, precise mechanisms of these processes remain unclear. Recent reports suggest that activation of aryl hydrocarbon receptor (AhR) signals by various ligands such as tryptophan derivatives can induce hyperimmune responses and are involved in autoimmunity. We investigated the effects of AhR signals on the process of lung fibrosis and changes in immunological features using a bleomycin (BLM)-induced lung fibrosis mouse model

Methods

Results

Conclusion