Airway Epithelial Transcription Factor NK2 Homeobox 1 Inhibits Mucous Cell Metaplasia and Th2 Inflammation

Perinatal Institute, Divisions of Neonatology, Perinatal, and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 05/2011; 184(4):421-9. DOI: 10.1164/rccm.201101-0106OC
Source: PubMed


Airway mucous cell metaplasia and chronic inflammation are pathophysiological features that influence morbidity and mortality associated with asthma and other chronic pulmonary disorders. Elucidation of the molecular mechanisms regulating mucous metaplasia and hypersecretion provides the scientific basis for diagnostic and therapeutic opportunities to improve the care of chronic pulmonary diseases.
To determine the role of the airway epithelial–specific transcription factor NK2 homeobox 1 (NKX2-1, also known as thyroid transcription factor-1 [TTF-1]) in mucous cell metaplasia and lung inflammation.
Expression of NKX2-1 in airway epithelial cells from patients with asthma was analyzed. NKX2-1 +/-gene targeted or transgenic mice expressing NKX2-1 in conducting airway epithelial cells were sensitized to the aeroallergen ovalbumin. In vitro studies were used to identify mechanisms by which NKX2-1 regulates mucous cell metaplasia and inflammation.
NKX2-1 was suppressed in airway epithelial cells from patients with asthma. Reduced expression of NKX2-1 in heterozygous NKX2-1 +/- gene targeted mice increased mucous metaplasia in the small airways after pulmonary sensitization to ovalbumin. Conversely, mucous cell metaplasia induced by aeroallergen was inhibited by expression of NKX2-1 in the respiratory epithelium in vivo. Genome-wide mRNA analysis of lung tissue from ovalbumin-treated mice demonstrated that NKX2-1 inhibited mRNAs associated with mucous metaplasia and Th2-regulated inflammation,including Spdef, Ccl17, and Il13. In vitro, NKX2-1 inhibited SPDEF, a critical regulator of airway mucous cell metaplasia,and the Th2 chemokine CCL26.
The present data demonstrate a novel function for NKX2-1 in a gene network regulating mucous cell metaplasia and allergic inflammation in the respiratory epithelium.

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Available from: Peter H Howarth, Nov 24, 2014
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    • "In collaboration with Jeffrey Whittset at the Children's Hospital in Cincinnati, we showed that TTF-1 was persistently suppressed in airway asthmatic epithelial cells which, in conditional TTF-1 deficient mice, translated into goblet cell induction and enhanced mucus secretion. In contrast, mucous metaplasia induced by aeroallergen was inhibited by epithelial over-expression of TTF-1.13 Application of transcriptomics to the airways of antigen sensitised and challenged TTF-1 over-expressing mice not only showed inhibition of genes controlling mucus production (e.g. "
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    • "Downstream of IL-13, several transcription factors, e.g., thyroid transcription factor (TTF)-1, Sam pointed domain-containing ETS transcription factor (SPDEF), and forkhead transcription factor (FOX)A2, regulate goblet cell development downstream of IL-13.60 While both TTF-1 and FOXA2 repress goblet cell metaplasia,61,62 SPDEF promotes goblet cell metaplasia by downregulating FOXA2 and TTF-1.62 Recently, increased SPDEF and decreased FOXA2 expression has been shown to contribute to the development of goblet cell hyperplasia in mouse models of asthma.63-66 "
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    • "Indeed, reduced Nkx2.1 expression in Clara cells may promote Clara to goblet cell transition . Accordingly, overexpression of Nkx2.1 in Clara cells inhibits allergen-induced mucous metaplasia preventing the loss of FOXA2 and the induction of SPDEF expression triggered by allergen sensitization [58]. "
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