Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation
Priya Rajavelu, … , Thomas R. Korfhagen, Jeffrey A. Whitsett
Priya Rajavelu, … , Thomas R. Korfhagen, Jeffrey A. Whitsett
Published April 13, 2015
Citation Information: J Clin Invest. 2015;125(5):2021-2031. https://doi.org/10.1172/JCI79422.
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Research Article Pulmonology

Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation

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.

Authors

Priya Rajavelu, Gang Chen, Yan Xu, Joseph A. Kitzmiller, Thomas R. Korfhagen, Jeffrey A. Whitsett

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Figure 1

SPDEF causes goblet cell differentiation, pulmonary inflammation, and AHR.

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SPDEF causes goblet cell differentiation, pulmonary inflammation, and AH...
Dams of Scgb1ab-rtTA TRE-Spdef (black bars) and control littermate single-transgenic mice (white bars) were placed on doxycycline from E16.5 to P15. (A) At P15, lung histology of the pups was assessed by H&E (n = 8) and BALF (n = 4) staining with Diff-Quik. Immunostaining for SPDEF, FOXA3, and MUC5B demonstrated extensive goblet cell differentiation (n = 8). (A and C) Cells isolated from BALF were stained with Diff-Quik and showed eosinophilic infiltrates. Data represent the mean ± SEM. *P < 0.05 compared with controls using an unpaired, 2-tailed Student’s t test. (B) AHR is represented as Penh in response to methacholine. Data represent the mean ± SEM of 6 mice per group. *P < 0.05 by 2-way ANOVA. (E) Flow cytometric analysis of lung cells obtained at P15 demonstrated increased numbers of SiglecF+CCR3+ in Scgb1a1-rtTA Spdef mice (black bar) compared with cell numbers detected in littermate control mice (white bar). (D and E) ST2+, IL-17RB+, and ICOS+ ILCs and total CD3+ and CD3+ IL-4–producing T cells were increased, and IFN-γ–producing CD3+ T cells were unaltered. Data represent the mean ± SEM. *P < 0.05 compared with controls using an unpaired, 2-tailed Student’s t test. n = 4/group. Examples of FACS analyses are provided in Supplemental Figure 1.