Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor expressed in the lungs that is activated by numerous xenobiotic, endogenous and dietary ligands. Although historically the AhR is known for mediating the deleterious response to the environmental pollutant dioxin, emerging evidence supports a prominent role for the AhR in numerous biological process including inflammation. We have shown that the AhR suppresses pulmonary neutrophilia in response to acute cigarette smoke exposure. Whether the AhR can also prevent lung inflammation from chronic smoke exposure is not known but highly relevant, given that people smoke for decades. Using our preclinical smoke model, we report that exposure to chronic cigarette smoke for 8-weeks or 4 months significantly increased pulmonary inflammation, the response of which was greater in Ahr−/− mice. Notably, there was an increased number of multinucleated giant cells (MNGCs) in smoke-exposed Ahr−/− mice without a change in cytokine levels. These data support a protective role for the AhR against the deleterious effects of cigarette smoke, warranting continued investigation into its therapeutic potential for chronic lung diseases.

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The Aryl Hydrocarbon Receptor Attenuates Acute Cigarette Smoke-Induced Airway Neutrophilia Independent of the Dioxin Response Element

Frontiers in Immunology ◽

10.3389/fimmu.2021.630427 ◽

2021 ◽

Vol 12 ◽

Author(s):

Angela Rico de Souza ◽

Hussein Traboulsi ◽

Xinyu Wang ◽

Jorg H. Fritz ◽

David H. Eidelman ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Cigarette Smoke ◽

Pulmonary Inflammation ◽

Cigarette Smoke Exposure ◽

Mouse Strains ◽

Chronic Obstructive ◽

Response Element ◽

Aryl Hydrocarbon ◽

Chronic Lung Diseases ◽

Anti Inflammatory

Cigarette smoke is a prevalent respiratory toxicant that remains a leading cause of death worldwide. Cigarette smoke induces inflammation in the lungs and airways that contributes to the development of diseases such as lung cancer and chronic obstructive pulmonary disease (COPD). Due to the presence of aryl hydrocarbon receptor (AhR) ligands in cigarette smoke, activation of the AhR has been implicated in driving this inflammatory response. However, we have previously shown that the AhR suppresses cigarette smoke-induced pulmonary inflammation, but the mechanism by which the AhR achieves its anti-inflammatory function is unknown. In this study, we use the AhR antagonist CH-223191 to inhibit AhR activity in mice. After an acute (3-day) cigarette smoke exposure, AhR inhibition was associated with significantly enhanced neutrophilia in the airways in response to cigarette smoke, mimicking the phenotype of AhR-deficient mice. We then used genetically-modified mouse strains which express an AhR that can bind ligand but either cannot translocate to the nucleus or bind its cognate response element, to show that these features of the AhR pathway are not required for the AhR to suppress pulmonary neutrophilia. Finally, using the non-toxic endogenous AhR ligand FICZ, we provide proof-of-concept that activation of pulmonary AhR attenuates smoke-induced inflammation. Collectively, these results support the importance of AhR activity in mediating its anti-inflammatory function in response to cigarette smoke. Further investigation of the precise mechanisms by which the AhR exerts is protective functions may lead to the development of therapeutic agents to treat people with chronic lung diseases that have an inflammatory etiology, but for which few therapeutic options exist.

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Hydroquinone Exposure Worsens Rheumatoid Arthritis through the Activation of the Aryl Hydrocarbon Receptor and Interleukin-17 Pathways

Antioxidants ◽

10.3390/antiox10060929 ◽

2021 ◽

Vol 10 (6) ◽

pp. 929

Author(s):

Cintia Scucuglia Heluany ◽

Paula Barbim Donate ◽

Ayda Henriques Schneider ◽

André Luis Fabris ◽

Renan Augusto Gomes ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

Aryl Hydrocarbon Receptor ◽

Cigarette Smoke ◽

Cigarette Smoke Exposure ◽

Interleukin 17 ◽

Aryl Hydrocarbon ◽

Tnf Α

Rheumatoid arthritis (RA) development is strongly associated with cigarette smoke exposure, which activates the aryl hydrocarbon receptor (AhR) as a trigger for Th17 inflammatory pathways. We previously demonstrated that the exposure to hydroquinone (HQ), one of the major compounds of cigarette tar, aggravates the arthritis symptomatology in rats. However, the mechanisms related to the HQ-related RA still remain elusive. Cell viability, cytokine secretion, and gene expression were measured in RA human fibroblast-like synoviocytes (RAHFLS) treated with HQ and stimulated or not with TNF-α. Antigen-induced arthritis (AIA) was also elicited in wild type (WT), AhR −/− or IL-17R −/− C57BL/6 mice upon daily exposure to nebulized HQ (25ppm) between days 15 to 21. At day 21, mice were challenged with mBSA and inflammatory parameters were assessed. The in vitro HQ treatment up-regulated TNFR1, TNFR2 expression, and increased ROS production. The co-treatment of HQ and TNF-α enhanced the IL-6 and IL-8 secretion. However, the pre-incubation of RAHFLS with an AhR antagonist inhibited the HQ-mediated cell proliferation and gene expression profile. About the in vivo approach, the HQ exposure worsened the AIA symptoms (edema, pain, cytokines secretion and NETs formation) in WT mice. These AIA effects were abolished in HQ-exposed AhR −/− and IL-17R −/− animals though. Our data demonstrated the harmful HQ influence over the onset of arthritis through the activation and proliferation of synoviocytes. The HQ-related RA severity was also associated with the activation of AhR and IL-17 pathways, highlighting how cigarette smoke compounds can contribute to the RA progression.

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