Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresponsiveness by inhibiting UPR transducers
Emily M. Nakada, Nirav R. Bhakta, Bethany R. Korwin-Mihavics, Amit Kumar, Nicolas Chamberlain, Sierra R. Bruno, David G. Chapman, Sidra M. Hoffman, Nirav Daphtary, Minara Aliyeva, Charles G. Irvin, Anne E. Dixon, Prescott G. Woodruff, Shantu Amin, Matthew E. Poynter, Dhimant H. Desai, Vikas Anathy
Emily M. Nakada, Nirav R. Bhakta, Bethany R. Korwin-Mihavics, Amit Kumar, Nicolas Chamberlain, Sierra R. Bruno, David G. Chapman, Sidra M. Hoffman, Nirav Daphtary, Minara Aliyeva, Charles G. Irvin, Anne E. Dixon, Prescott G. Woodruff, Shantu Amin, Matthew E. Poynter, Dhimant H. Desai, Vikas Anathy
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Research Article Inflammation Pulmonology

Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresponsiveness by inhibiting UPR transducers

Abstract

Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite–induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.

Authors

Emily M. Nakada, Nirav R. Bhakta, Bethany R. Korwin-Mihavics, Amit Kumar, Nicolas Chamberlain, Sierra R. Bruno, David G. Chapman, Sidra M. Hoffman, Nirav Daphtary, Minara Aliyeva, Charles G. Irvin, Anne E. Dixon, Prescott G. Woodruff, Shantu Amin, Matthew E. Poynter, Dhimant H. Desai, Vikas Anathy

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Figure 2

TUDCA attenuates AHR, IL-4, IL-5, IL-13, IgE production, and mucus metaplasia.

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TUDCA attenuates AHR, IL-4, IL-5, IL-13, IgE production, and mucus metap...
(A–C) AHR by FlexiVent in response to increasing concentrations of methacholine (PBS n = 11; HDM n = 16; and HDM plus TUDCA n = 7 mice from 2 experiments). One-way ANOVA, Tukey’s post hoc test. *P < 0.05 vs. PBS group; #P < 0.05 vs. HDM group (mice were removed in Rn, G, and H; in HDM plus TUDCA group n = 2 based on noncompliance with coefficient of determination [COD] value). (D–H) Quantification of cytokines by ELISA from lung homogenates and IgE from serum; n = 10 mice/group from 2 experiments (outliers removed in IL-5; PBS: n = 1). (I and J) Muc5ac and Clca1 expression in the lungs assessed by reverse transcription quantitative PCR (RT-qPCR); n = 7 mice from 2 experiments. (K) Representative images of PAS-stained lungs. Scale bar: 25 μm. (L) Quantification of PAS-stained lungs; n = 3–7 representative mice from 2 experiments. (D–H and J) Kruskal-Wallis, 2-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli. Two comparisons, both with the HDM group. *P < 0.05 vs. PBS group; #P < 0.05 vs. HDM group. Rn, Newtonian resistance; G, tissue damping; H, tissue elastance; ns, not significant vs. HDM plus PBS group. Error bars represent ± SEM.