Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation

J Clin Invest. 2015 May;125(5):2021-31. doi: 10.1172/JCI79422. Epub 2015 Apr 13.

Abstract

Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33, Csf2, thymic stromal lymphopoietin (Tslp), and Ccl20 transcripts. Increased Il4, Il13, Ccl17, and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult Spdef(-/-) mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Antigens, Dermatophagoides / toxicity*
  • Cell Differentiation
  • Chemokine CCL20 / biosynthesis
  • Chemokine CCL20 / genetics
  • Chemotaxis, Leukocyte
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Dendritic Cells / immunology
  • Eosinophils / physiology
  • Epithelial Cells / metabolism*
  • Goblet Cells / physiology*
  • Hepatocyte Nuclear Factor 3-gamma / physiology
  • Interleukins / biosynthesis
  • Interleukins / genetics
  • Lung / immunology*
  • Metaplasia
  • Methacholine Chloride / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / physiology*
  • Pulmonary Eosinophilia / etiology
  • Pulmonary Eosinophilia / immunology*
  • Pulmonary Eosinophilia / metabolism
  • Pulmonary Eosinophilia / pathology
  • Recombinant Fusion Proteins / metabolism
  • Th2 Cells / immunology*
  • Transgenes

Substances

  • Antigens, Dermatophagoides
  • CCL20 protein, mouse
  • Chemokine CCL20
  • Cytokines
  • Foxa3 protein, mouse
  • Interleukins
  • Proto-Oncogene Proteins c-ets
  • Recombinant Fusion Proteins
  • Spdef protein, mouse
  • Methacholine Chloride
  • Hepatocyte Nuclear Factor 3-gamma
  • thymic stromal lymphopoietin