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Distinct Roles of FOXA2 and FOXA3 in Allergic Airway Disease and Asthma

¹ Lung Biology Center, University of California San Francisco, San Francisco, California; ² Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Kyeonggi-Do, Korea; and ³ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to David J. Erle, M.D., UCSF Mail Code 2922, Rock Hall, Room 548D, 1550 4th Street, San Francisco, CA 94143. E-mail: david.erle{at}ucsf.edu

Rationale: Increased production of mucus is a prominent feature of asthma. IL-13–driven mucous cell metaplasia is associated with decreased expression of the transcription factor FOXA2 and increased expression of the related transcription factor FOXA3 in animal and cell culture models.

Objectives: Establish how changes in FOXA2 and FOXA3 expression contribute to mucous metaplasia and determine whether FOXA2 and FOXA3 expression is altered in asthma.

Methods: Mice expressing a Foxa2 transgene in airway epithelial cells and mice deficient in Foxa3 were analyzed after allergen sensitization and challenge. Expression of FOXA2, FOXA3, MUC5AC, and the highly IL-13–inducible gene CLCA1 was analyzed in airway biopsies from subjects with asthma and control subjects.

Measurements and Main Results: Expression of a Foxa2 transgene reduced allergen-induced mucous metaplasia by 45% compared with control transgenic mice (P < 0.05) whereas inactivation of Foxa3 had no detectable effects on mucous metaplasia. Expression of FOXA2 was reduced in subjects with asthma and was negatively correlated with MUC5AC and CLCA1 levels in subjects with asthma. In contrast, FOXA3 expression was not significantly correlated with MUC5AC and was positively correlated with CLCA1.

Conclusions: Increasing Foxa2 expression reduced mucous metaplasia in an allergic mouse model. Subjects with asthma had decreased FOXA2 expression, suggesting that therapeutic approaches that increase FOXA2 expression or function could be beneficial for reducing mucus production in asthma. Unlike FOXA2, FOXA3 did not regulate mucous metaplasia.

Key Words: mucus • asthma • transcription factor • lung

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject In mouse asthma models, mucus production is associated with decreased levels of the FOXA2 transcription factor and increased levels of the related protein FOXA3 in airway epithelial cells. What This Study Adds to the Field FOXA2 expression is reduced in humans with asthma and increasing FOXA2 expression reduces mucus in a mouse asthma model. FOXA3 did not regulate mucus levels in the same model.