Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease.
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.
Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Derek E
DE
Byers
Jennifer
J
Alexander-Brett
Anand C
AC
Patel
Eugene
E
Agapov
Geoffrey
G
Dang-Vu
Xiaohua
X
Jin
Kangyun
K
Wu
Yingjian
Y
You
Yael
Y
Alevy
Jean-Philippe
JP
Girard
Thaddeus S
TS
Stappenbeck
G Alexander
GA
Patterson
Richard A
RA
Pierce
Steven L
SL
Brody
Michael J
MJ
Holtzman
D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018123:Receptors, Interleukin / Q000378:metabolism; D020545:Respiratory Mucosa / Q000473:pathology; D018874:Spheroids, Cellular / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D059467:Transcriptome; D015854:Up-Regulation
C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin