Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease
Derek E. Byers, … , Steven L. Brody, Michael J. Holtzman
Derek E. Byers, … , Steven L. Brody, Michael J. Holtzman
Published August 15, 2013
Citation Information: J Clin Invest. 2013;123(9):3967-3982. https://doi.org/10.1172/JCI65570.
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Research Article

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

Abstract

Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13–dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production.

Authors

Derek E. Byers, Jennifer Alexander-Brett, Anand C. Patel, Eugene Agapov, Geoffrey Dang-Vu, Xiaohua Jin, Kangyun Wu, Yingjian You, Yael Alevy, Jean-Philippe Girard, Thaddeus S. Stappenbeck, G. Alexander Patterson, Richard A. Pierce, Steven L. Brody, Michael J. Holtzman

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Figure 6

Selective increase in IL-33–expressing airway epithelial cells in COPD.

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Selective increase in IL-33–expressing airway epithelial cells in COPD. ...
(A). Levels of IL33, IL25, and TSLP mRNA in non-COPD (n = 7) and COPD (n = 15) lung tissues. (B) Levels of IL-33, determined by ELISA, using non-COPD (n = 16 samples from 9 subjects) versus COPD (n = 17 samples from 11 subjects) lung lysates. (C) Levels of IL33 mRNA in lung cells before FACS (Pre-sort Cells) and the indicated cell populations purified by FACS from COPD subjects (n = 4) using labeled anti-CD45 and anti-CD14 mAb. (D) Representative photomicrographs of sections of airway epithelium immunostained for IL-33 with DAB (brown) reporter and counterstained with tartrazine (yellow). (E) Number of IL-33+ cell nuclei per millimeter basement membrane in non-COPD (n = 6) versus COPD (n = 10) lung tissues. (F) Representative photomicrographs of non-COPD and COPD airway epithelium sections immunostained for IL-33 with red (Alexa Fluor 594) reporter; costained for MUC5AC, SCGB1A1, or FOXJ1 with green (Alexa Fluor 488) reporter; and counterstained with DAPI (blue). (A, B, and E) Box represents 25th–75th percentile; line represents median; “+” represents mean; whiskers represent range. (C) Bars represent mean ± SEM. P values were derived from unpaired Student’s t test, but comparisons of medians were also made using Mann-Whitney U test with similar results. Scale bars: 100 μm.