TY - JOUR
T1 - Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease
AU - Byers, Derek E.
AU - Alexander-Brett, Jennifer
AU - Patel, Anand C.
AU - Agapov, Eugene
AU - Dang-Vu, Geoffrey
AU - Jin, Xiaohua
AU - Wu, Kangyun
AU - You, Yingjian
AU - Alevy, Yael
AU - Girard, Jean Philippe
AU - Stappenbeck, Thaddeus S.
AU - Patterson, G. Alexander
AU - Pierce, Richard A.
AU - Brody, Steven L.
AU - Holtzman, Michael J.
PY - 2013/9/3
Y1 - 2013/9/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84883537459&partnerID=8YFLogxK
U2 - 10.1172/JCI65570
DO - 10.1172/JCI65570
M3 - Article
C2 - 23945235
AN - SCOPUS:84883537459
SN - 0021-9738
VL - 123
SP - 3967
EP - 3982
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -