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

Abstract

Background: Interstitial 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 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: BLM 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.Results: Both 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.Conclusions: Our 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.

The Roles of Immune Cells in the Pathogenesis of Fibrosis

“…A natural AhR agonist norisoboldine promoted Tregs differentiation through regulating glycolysis and NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway during colitis development [ 106 ]. A recent study indicated a role of AhR signal in regulating Tregs functions during fibrogenic responses [ 107 ]. Bleomycin-challenged mice with treatment of FICZ, a natural AhR ligand, exhibited increased number of Tregs with attenuated lung fibrosis, suggesting a therapeutic potential of targeting AhR for treating fibrotic diseases [ 107 ].…”

“…A recent study indicated a role of AhR signal in regulating Tregs functions during fibrogenic responses [ 107 ]. Bleomycin-challenged mice with treatment of FICZ, a natural AhR ligand, exhibited increased number of Tregs with attenuated lung fibrosis, suggesting a therapeutic potential of targeting AhR for treating fibrotic diseases [ 107 ]. Tregs also exerted protective functions against coxsackievirus B3-induced cardiac fibrosis via secretion of IL-10, an important regulatory cytokine [ 108 ].…”

Dexamethasone and lactoferrin induced PMN-MDSCs relieved inflammatory adverse events of anti-cancer therapy without tumor promotion

“…Sections (5 mm) of paraffin-embedded lung tissues were stained with hematoxylin and eosin (H&E) according to standard histological procedures and optical observation of the microscopic lung structure was performed blindly by an expert pathologist. Lung inflammation was assigned a score from 0 to 3 based on the absence(0) or presence to a mild 1 , moderate 2 , severe 3 degree of focal thickening of alveolar membranes, congestion, and interstitial and intra-alveolar neutrophil infiltration. A total cumulative histology score was determined 2 .…”

“…The adverse effects of chemotherapy limit the quality of life and survival of cancer patients. Among them, kidney failure 1 , interstitial pneumonia 2 , and allergic pneumonitis 3 feature an over-activated immune system and inflammation, and often require permanent cessation of the ongoing therapy, including cisplatin, bleomycin, and immune checkpoint inhibitors (ICIs) 4 . Glucocorticoids are considered as fundamental choice of drugs for the prevention and treatment for such inflammatory adverse events 1 , 5 , 6 .…”

Potential Benefits of Tryptophan Metabolism to the Efficacy of Tocilizumab in COVID-19

“…Notably, AhR is widely expressed in immune cells where the activated receptor can tip the balance regulatory and inflammatory T cells in favor of the former subset. Administration of AhR agonists alleviated immunopathology in various animal models, such as experimental autoimmune encephalomyelitis, experimental colitis (Quintana et al, 2008) and, recently, a model of pulmonary fibrosis (Takei et al, 2020). Kyn is also a potent vasodilator of systemic arteries and has been found to be significantly increased in pulmonary arterial hypertension patients.…”