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Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity

Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity
Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity
Rationale: Goblet cell metaplasia accompanies common pulmonary disorders that are prone to recurrent viral infections. Mechanisms regulating both goblet cell metaplasia and susceptibility to viral infection associated with chronic lung diseases are incompletely understood.

Objectives: We sought to identify the role of the transcription factor FOXA3 in regulation of goblet cell metaplasia and pulmonary innate immunity.

Methods: FOXA3 was identified in airways from patients with asthma and chronic obstructive pulmonary disease. We produced transgenic mice conditionally expressing Foxa3 in airway epithelial cells and developed human bronchial epithelial cells expressing Foxa3. Foxa3-regulated genes were identified by immunostaining, Western blotting, and RNA analysis. Direct binding of FOXA3 to target genes was identified by chromatin immunoprecipitation sequencing correlated with RNA sequencing.

Measurements and Main Results: FOXA3 was highly expressed in airway goblet cells from patients with asthma and chronic obstructive pulmonary disease. FOXA3 was induced by either IL-13 or rhinovirus. Foxa3 induced goblet cell metaplasia and enhanced expression of a network of genes mediating mucus production. Paradoxically, FOXA3 inhibited rhinovirus-induced IFN production, IRF-3 phosphorylation, and IKK? expression and inhibited viral clearance and expression of genes required for antiviral defenses, including MDA5, RIG-I, TLR3, IRF7/9, and nuclear factor-?B.

Conclusions: FOXA3 induces goblet cell metaplasia in response to infection or Th2 stimulation. Suppression of IFN signaling by FOXA3 provides a plausible mechanism that may serve to limit ongoing Th1 inflammation during the resolution of acute viral infection; however, inhibition of innate immunity by FOXA3 may contribute to susceptibility to viral infections associated with chronic lung disorders accompanied by chronic goblet cell metaplasia.
rhinovirus, ifn, transcription factors, mucus
1073-449X
301-313
Chen, Gang
83a5c46f-13cc-4be3-ad5b-698a69e82b8e
Korfhagen, Thomas R.
c24855a1-36f0-47af-9d5a-5524d754d4bb
Karp, Christopher L.
9d26ac22-9e31-46c8-aa0d-8f9b55ee708d
Impey, Soren
912f6f67-f61d-4cb3-b727-c6a7520771e1
Xu, Yan
2b4952f1-3855-4a5d-a8b0-777561a292e1
Randell, Scott H.
7b962dd6-02c0-4ee5-b5be-e049ed97e621
Kitzmiller, Joseph
49d4d5d6-f2aa-4124-b4cd-da104dbfe738
Maeda, Yutaka
93d2b566-1f36-4c02-a1a4-8cc8a7e89e9b
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Sridharan, Anusha
41c79789-05b6-4a8f-9669-acf95cfa2da5
Senft, Albert P.
324dfc5a-d40d-448e-80ac-d6caf92d67fd
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Chen, Gang
83a5c46f-13cc-4be3-ad5b-698a69e82b8e
Korfhagen, Thomas R.
c24855a1-36f0-47af-9d5a-5524d754d4bb
Karp, Christopher L.
9d26ac22-9e31-46c8-aa0d-8f9b55ee708d
Impey, Soren
912f6f67-f61d-4cb3-b727-c6a7520771e1
Xu, Yan
2b4952f1-3855-4a5d-a8b0-777561a292e1
Randell, Scott H.
7b962dd6-02c0-4ee5-b5be-e049ed97e621
Kitzmiller, Joseph
49d4d5d6-f2aa-4124-b4cd-da104dbfe738
Maeda, Yutaka
93d2b566-1f36-4c02-a1a4-8cc8a7e89e9b
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Sridharan, Anusha
41c79789-05b6-4a8f-9669-acf95cfa2da5
Senft, Albert P.
324dfc5a-d40d-448e-80ac-d6caf92d67fd
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b

Chen, Gang, Korfhagen, Thomas R., Karp, Christopher L., Impey, Soren, Xu, Yan, Randell, Scott H., Kitzmiller, Joseph, Maeda, Yutaka, Haitchi, Hans Michael, Sridharan, Anusha, Senft, Albert P. and Whitsett, Jeffrey A. (2014) Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity. American Journal of Respiratory and Critical Care Medicine, 189 (3), 301-313. (doi:10.1164/rccm.201306-1181OC). (PMID:24392884)

Record type: Article

Abstract

Rationale: Goblet cell metaplasia accompanies common pulmonary disorders that are prone to recurrent viral infections. Mechanisms regulating both goblet cell metaplasia and susceptibility to viral infection associated with chronic lung diseases are incompletely understood.

Objectives: We sought to identify the role of the transcription factor FOXA3 in regulation of goblet cell metaplasia and pulmonary innate immunity.

Methods: FOXA3 was identified in airways from patients with asthma and chronic obstructive pulmonary disease. We produced transgenic mice conditionally expressing Foxa3 in airway epithelial cells and developed human bronchial epithelial cells expressing Foxa3. Foxa3-regulated genes were identified by immunostaining, Western blotting, and RNA analysis. Direct binding of FOXA3 to target genes was identified by chromatin immunoprecipitation sequencing correlated with RNA sequencing.

Measurements and Main Results: FOXA3 was highly expressed in airway goblet cells from patients with asthma and chronic obstructive pulmonary disease. FOXA3 was induced by either IL-13 or rhinovirus. Foxa3 induced goblet cell metaplasia and enhanced expression of a network of genes mediating mucus production. Paradoxically, FOXA3 inhibited rhinovirus-induced IFN production, IRF-3 phosphorylation, and IKK? expression and inhibited viral clearance and expression of genes required for antiviral defenses, including MDA5, RIG-I, TLR3, IRF7/9, and nuclear factor-?B.

Conclusions: FOXA3 induces goblet cell metaplasia in response to infection or Th2 stimulation. Suppression of IFN signaling by FOXA3 provides a plausible mechanism that may serve to limit ongoing Th1 inflammation during the resolution of acute viral infection; however, inhibition of innate immunity by FOXA3 may contribute to susceptibility to viral infections associated with chronic lung disorders accompanied by chronic goblet cell metaplasia.

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More information

Accepted/In Press date: 13 December 2013
e-pub ahead of print date: 6 January 2014
Published date: 1 February 2014
Keywords: rhinovirus, ifn, transcription factors, mucus
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 386153
URI: https://eprints.soton.ac.uk/id/eprint/386153
ISSN: 1073-449X
PURE UUID: a46418f0-4ad3-4ba5-93d0-70675e79a2c9
ORCID for Hans Michael Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

Catalogue record

Date deposited: 28 Jan 2016 14:35
Last modified: 05 Nov 2019 01:52

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Contributors

Author: Gang Chen
Author: Thomas R. Korfhagen
Author: Christopher L. Karp
Author: Soren Impey
Author: Yan Xu
Author: Scott H. Randell
Author: Joseph Kitzmiller
Author: Yutaka Maeda
Author: Anusha Sridharan
Author: Albert P. Senft
Author: Jeffrey A. Whitsett

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