Allergen induces pulmonary neuroendocrine cell hyperplasia in a model of asthma
Estelle Kim, Brian K. Wells, Hannah Indralingam, Yujuan Su, Jamie Verheyden, Xin Sun
Estelle Kim, Brian K. Wells, Hannah Indralingam, Yujuan Su, Jamie Verheyden, Xin Sun
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Research Article Cell biology Development Pulmonology

Allergen induces pulmonary neuroendocrine cell hyperplasia in a model of asthma

Abstract

Asthma is characterized by exacerbated response to triggers such as allergen. While pulmonary neuroendocrine cells (PNECs), a rare population of airway epithelial cells, are essential for amplifying allergen-induced asthma response, how PNECs are regulated to achieve this role remains poorly understood. Here we show that in the adult mouse airway, inactivation of achaete-scute-like protein 1 gene in PNECs led to loss of these cells. Intriguingly, exposure of these mutants to house dust mites (HDM), a common allergen, led to reappearance of PNECs. Similarly, exposure of wild-type mice to HDM led to PNEC hyperplasia, a result of proliferation of existing PNECs and transdifferentiation from club cells. Single-cell RNA-Seq experiments revealed PNEC heterogeneity, including the emergence of an allergen-induced PNEC subtype. Notch signaling was downregulated in HDM-treated airway, and treatment with Notch agonist prevented PNEC hyperplasia. These findings together suggest that HDM-induced PNEC hyperplasia may contribute to exacerbated asthma response.

Authors

Estelle Kim, Brian K. Wells, Hannah Indralingam, Yujuan Su, Jamie Verheyden, Xin Sun

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Figure 3

Proliferation and club cell transdifferentiation contribute to PNEC hyperplasia in WT mice following allergen challenge.

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Proliferation and club cell transdifferentiation contribute to PNEC hype...
(A) Representative images of WT lung sections stained with anti-CGRP antibody. (B and C) Quantification of PNEC numbers based on CGRP staining or Ascl1-lineage. One-way ANOVA was used (n = 3–8 for each group). (D) Representative images of Ascl1-lineaged lung sections exposed to saline or HDM stained with anti-Ki67 antibody to detect proliferation in PNEC clusters on top row. Arrowheads point to proliferating PNECs on top row. Representative images of Scgb1a1-lineaged lung sections exposed to saline or HDM stained with anti-CGRP antibody to trace club cell transdifferentiation to PNECs on bottom row. Arrowheads point to transdifferentiating PNECs on bottom row. (E) Quantification of Ascl1-lineage overlap with Ki67+ cells over the total of Ascl1-lineaged cells. Student’s t test was used (n = 3 for each group). (F) Quantification of Scgb1a1-lineage overlap with CGRP+ cells over the total of CGRP+ cells. Student’s t test was used (n = 3, 4 for each group). (G) Representative images of Ascl1 lineage lung sections exposed to saline or HDM stained with anti-CGRP antibody. (H) Representative images of protruding NEBs marked by anti-CGRP antibody in saline or HDM-challenged lung sections. Asterisks represent gap between epithelial layer and the subjacent mesenchymal cells. (I) Quantification of protruding NEBs over the total number of PNEC clusters. One-way ANOVA was used (n = 3–5 for each group). Each data point represents the average value of ~25 sections from 1 lung. ** for P < 0.01, *** for P < 0.001, and **** for P < 0.0001. Error bars represent mean ± SD. Arrowheads point to PNECs with elongated morphology following allergen challenge. Scale bar size 50 μm.