Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness 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

Research output: Contribution to journalArticle

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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 UPRassociated 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.

Original languageEnglish (US)
Article numbere98101
JournalJCI Insight
Volume4
Issue number9
DOIs
StatePublished - Jan 1 2019

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Unfolded Protein Response
Transducers
Bile Acids and Salts
Allergens
Inflammation
Activating Transcription Factor 6
Asthma
Pyroglyphidae
Healthy Volunteers
Metaplasia
Mucus

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Nakada, E. M., Bhakta, N. R., Korwin-Mihavics, B. R., Kumar, A., Chamberlain, N., Bruno, S. R., ... Anathy, V. (2019). Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers. JCI Insight, 4(9), [e98101]. https://doi.org/10.1172/jci.insight.98101
Nakada, Emily M. ; Bhakta, Nirav R. ; Korwin-Mihavics, Bethany R. ; Kumar, Amit ; Chamberlain, Nicolas ; Bruno, Sierra R. ; Chapman, David G. ; Hoffman, Sidra M. ; Daphtary, Nirav ; Aliyeva, Minara ; Irvin, Charles G. ; Dixon, Anne E. ; Woodruff, Prescott G. ; Amin, Shantu ; Poynter, Matthew E. ; Desai, Dhimant H. ; Anathy, Vikas. / Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers. In: JCI Insight. 2019 ; Vol. 4, No. 9.
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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 UPRassociated 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.",
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Nakada, EM, Bhakta, NR, Korwin-Mihavics, BR, Kumar, A, Chamberlain, N, Bruno, SR, Chapman, DG, Hoffman, SM, Daphtary, N, Aliyeva, M, Irvin, CG, Dixon, AE, Woodruff, PG, Amin, S, Poynter, ME, Desai, DH & Anathy, V 2019, 'Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers', JCI Insight, vol. 4, no. 9, e98101. https://doi.org/10.1172/jci.insight.98101

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

In: JCI Insight, Vol. 4, No. 9, e98101, 01.01.2019.

Research output: Contribution to journalArticle

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T1 - Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers

AU - Nakada, Emily M.

AU - Bhakta, Nirav R.

AU - Korwin-Mihavics, Bethany R.

AU - Kumar, Amit

AU - Chamberlain, Nicolas

AU - Bruno, Sierra R.

AU - Chapman, David G.

AU - Hoffman, Sidra M.

AU - Daphtary, Nirav

AU - Aliyeva, Minara

AU - Irvin, Charles G.

AU - Dixon, Anne E.

AU - Woodruff, Prescott G.

AU - Amin, Shantu

AU - Poynter, Matthew E.

AU - Desai, Dhimant H.

AU - Anathy, Vikas

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N2 - 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 UPRassociated 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.

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