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SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia

SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia
SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia
Airway mucus plays a critical role in clearing inhaled toxins, particles, and pathogens. Diverse toxic, inflammatory, and infectious insults induce airway mucus secretion and goblet cell metaplasia to preserve airway sterility and homeostasis. However, goblet cell metaplasia, mucus hypersecretion, and airway obstruction are integral features of inflammatory lung diseases, including asthma, chronic obstructive lung disease, and cystic fibrosis, which cause an immense burden of morbidity and mortality. These chronic lung diseases are united by susceptibility to microbial colonization and recurrent airway infections. Whether these twinned phenomena (mucous metaplasia, compromised host defenses) are causally related has been unclear. Here, we demonstrate that SAM pointed domain ETS factor (SPDEF) was induced by rhinoviral infection of primary human airway cells and that cytoplasmic activities of SPDEF, a transcriptional regulator of airway goblet cell metaplasia, inhibited Toll-like receptor (TLR) activation of epithelial cells. SPDEF bound to and inhibited activities of TLR signaling adapters, MyD88 and TRIF, inhibiting MyD88-induced cytokine production and TRIF-induced interferon ? production. Conditional expression of SPDEF in airway epithelial cells in vivo inhibited LPS-induced neutrophilic infiltration and bacterial clearance. SPDEF-mediated inhibition of both TLR and type I interferon signaling likely protects the lung against inflammatory damage when inciting stimuli are not eradicated. Present findings provide, at least in part, a molecular explanation for increased susceptibility to infection in lung diseases associated with mucous metaplasia and a mechanism by which patients with florid mucous metaplasia may tolerate microbial burdens that are usually associated with fulminant inflammatory disease in normal hosts.
0027-8424
16630-16635
Korfhagen, T.R.
7c573355-7153-4ac1-be25-996e4a3f943a
Kitzmiller, J.
2b707e21-b206-4c65-bd43-0e914c3f1507
Chen, G.
ae218ce4-4fea-4495-9520-0e2111c5ce6e
Sridharan, A.
79818b99-090a-45af-aa8b-a805f6a57644
Haitchi, H.M.
68dadb29-305d-4236-884f-e9c93f4d78fe
Hegde, R.S.
099702d8-9743-4808-9ed2-88789e49e8a4
Divanovic, S.
5b0c5591-d4d8-4106-93ec-2481cd94a611
Karp, C.L.
85064c6d-630d-4d39-8e1e-18159b03631f
Whitsett, J.A.
3fc6684d-66e9-43b3-98da-2c4c6236fcc3
Korfhagen, T.R.
7c573355-7153-4ac1-be25-996e4a3f943a
Kitzmiller, J.
2b707e21-b206-4c65-bd43-0e914c3f1507
Chen, G.
ae218ce4-4fea-4495-9520-0e2111c5ce6e
Sridharan, A.
79818b99-090a-45af-aa8b-a805f6a57644
Haitchi, H.M.
68dadb29-305d-4236-884f-e9c93f4d78fe
Hegde, R.S.
099702d8-9743-4808-9ed2-88789e49e8a4
Divanovic, S.
5b0c5591-d4d8-4106-93ec-2481cd94a611
Karp, C.L.
85064c6d-630d-4d39-8e1e-18159b03631f
Whitsett, J.A.
3fc6684d-66e9-43b3-98da-2c4c6236fcc3

Korfhagen, T.R., Kitzmiller, J., Chen, G., Sridharan, A., Haitchi, H.M., Hegde, R.S., Divanovic, S., Karp, C.L. and Whitsett, J.A. (2012) SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia. Proceedings of the National Academy of Sciences, 109 (41), 16630-16635. (doi:10.1073/pnas.1208092109). (PMID:23012424)

Record type: Article

Abstract

Airway mucus plays a critical role in clearing inhaled toxins, particles, and pathogens. Diverse toxic, inflammatory, and infectious insults induce airway mucus secretion and goblet cell metaplasia to preserve airway sterility and homeostasis. However, goblet cell metaplasia, mucus hypersecretion, and airway obstruction are integral features of inflammatory lung diseases, including asthma, chronic obstructive lung disease, and cystic fibrosis, which cause an immense burden of morbidity and mortality. These chronic lung diseases are united by susceptibility to microbial colonization and recurrent airway infections. Whether these twinned phenomena (mucous metaplasia, compromised host defenses) are causally related has been unclear. Here, we demonstrate that SAM pointed domain ETS factor (SPDEF) was induced by rhinoviral infection of primary human airway cells and that cytoplasmic activities of SPDEF, a transcriptional regulator of airway goblet cell metaplasia, inhibited Toll-like receptor (TLR) activation of epithelial cells. SPDEF bound to and inhibited activities of TLR signaling adapters, MyD88 and TRIF, inhibiting MyD88-induced cytokine production and TRIF-induced interferon ? production. Conditional expression of SPDEF in airway epithelial cells in vivo inhibited LPS-induced neutrophilic infiltration and bacterial clearance. SPDEF-mediated inhibition of both TLR and type I interferon signaling likely protects the lung against inflammatory damage when inciting stimuli are not eradicated. Present findings provide, at least in part, a molecular explanation for increased susceptibility to infection in lung diseases associated with mucous metaplasia and a mechanism by which patients with florid mucous metaplasia may tolerate microbial burdens that are usually associated with fulminant inflammatory disease in normal hosts.

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Published date: 24 September 2012
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 352554
URI: http://eprints.soton.ac.uk/id/eprint/352554
ISSN: 0027-8424
PURE UUID: e7bcf2d5-3413-48ee-9fae-112c2f83e854
ORCID for H.M. Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

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Date deposited: 15 May 2013 13:39
Last modified: 10 Dec 2019 01:47

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Contributors

Author: T.R. Korfhagen
Author: J. Kitzmiller
Author: G. Chen
Author: A. Sridharan
Author: H.M. Haitchi ORCID iD
Author: R.S. Hegde
Author: S. Divanovic
Author: C.L. Karp
Author: J.A. Whitsett

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