Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation
Priya Rajavelu, Gang Chen, Yan Xu, Joseph A. Kitzmiller, Thomas R. Korfhagen, Jeffrey A. Whitsett
Priya Rajavelu, Gang Chen, Yan Xu, Joseph A. Kitzmiller, Thomas R. Korfhagen, Jeffrey A. Whitsett
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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 3

SPDEF is required for Th2 inflammatory responses, AHR, and recruitment of ST2+ ILCs and IL-4+, IL-13+, and IL-17+ T cells in response to HDM extract in adult mice.

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SPDEF is required for Th2 inflammatory responses, AHR, and recruitment o...
HDM extract (100 μg) was administered i.n. daily for 3 days to adult control and Spdef–/– mice, which were sacrificed 2 days later. (A) Decreased mucous metaplasia and inflammatory responses to HDM were seen in Spdef–/– mice. (A and C) BALF cells (n = 4) were stained with Diff-Quik, which showed eosinophilic and neutrophilic infiltrates, and differential cell counts were quantified. Goblet cell differentiation (A) and the increase in Acta2 mRNA (Table 3) caused by HDM challenge were modestly decreased in Spdef–/– mice. (B) AHR was decreased in Spdef–/– mice. Data represent the mean ± SEM. Significance was analyzed using 2-way ANOVA with Bonferroni’s post tests. n = 6/group. (D and E) Flow analysis of lung cells from Spdef+/+ (white bars) and Spdef–/– mice (black bars) after HDM challenge. CD45+ and CD3+ cell numbers were not altered, and ST2+ ILC numbers were decreased. (E) Numbers of IL-4+, IL-13+, and IL-17+ T cells were decreased in Spdef–/– mice. Gating strategies are depicted in Supplemental Figure 1. Data represent the mean ± SEM. *P < 0.05 compared with controls using an unpaired, 2-tailed Student’s t test. n = 4/group.