TY - JOUR
T1 - Basophils trigger emphysema development in a murine model of COPD through IL-4–mediated generation of MMP-12–producing macrophages
AU - Shibata, Sho
AU - Miyake, Kensuke
AU - Tateishi, Tomoya
AU - Yoshikawa, Soichiro
AU - Yamanishi, Yoshinori
AU - Miyazaki, Yasunari
AU - Inase, Naohiko
AU - Karasuyama, Hajime
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank N. Mukaida and W. A. Kuziel for providing Ccr2−/− mice, R. Sasaki and H. Ohtsuka for technical support, the members of the H.K. laboratory for helpful discussions, and M. Kinoshita for secretarial assistance. This work was supported by a research grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology (15H05786; to H.K.).
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/12/18
Y1 - 2018/12/18
N2 - Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has generally been considered a non-Th2-type lung disorder, characterized by progressive airflow limitation with inflammation and emphysema, but its cellular and molecular mechanism remains ill defined, compared with that of asthma characterized by reversible airway obstruction. Here we show a previously unappreciated role for basophils at the initiation phase of emphysema formation in an elastase-induced murine model of COPD in that basophils represent less than 1% of lung-infiltrating cells. Intranasal elastase instillation elicited the recruitment of monocytes to the lung, followed by differentiation into interstitial macrophages (IMs) but rarely alveolar macrophages (AMs). Matrix metalloproteinase-12 (MMP-12) contributing to emphysema formation was highly expressed by IMs rather than AMs, in contrast to the prevailing assumption. Experiments using a series of genetically engineered mice suggested that basophil-derived IL-4, a Th2 cytokine, acted on lung-infiltrating monocytes to promote their differentiation into MMP-12–producing IMs that resulted in the destruction of alveolar walls and led to emphysema development. Indeed, mice deficient for IL-4 only in basophils failed to generate pathogenic MMP-12–producing IMs and hence develop emphysema. Thus, the basophil-derived IL-4/monocyte–derived IM/MMP-12 axis plays a crucial role in emphysema formation and therefore may be a potential target to slow down emphysema progression at the initiation phase of COPD.
AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has generally been considered a non-Th2-type lung disorder, characterized by progressive airflow limitation with inflammation and emphysema, but its cellular and molecular mechanism remains ill defined, compared with that of asthma characterized by reversible airway obstruction. Here we show a previously unappreciated role for basophils at the initiation phase of emphysema formation in an elastase-induced murine model of COPD in that basophils represent less than 1% of lung-infiltrating cells. Intranasal elastase instillation elicited the recruitment of monocytes to the lung, followed by differentiation into interstitial macrophages (IMs) but rarely alveolar macrophages (AMs). Matrix metalloproteinase-12 (MMP-12) contributing to emphysema formation was highly expressed by IMs rather than AMs, in contrast to the prevailing assumption. Experiments using a series of genetically engineered mice suggested that basophil-derived IL-4, a Th2 cytokine, acted on lung-infiltrating monocytes to promote their differentiation into MMP-12–producing IMs that resulted in the destruction of alveolar walls and led to emphysema development. Indeed, mice deficient for IL-4 only in basophils failed to generate pathogenic MMP-12–producing IMs and hence develop emphysema. Thus, the basophil-derived IL-4/monocyte–derived IM/MMP-12 axis plays a crucial role in emphysema formation and therefore may be a potential target to slow down emphysema progression at the initiation phase of COPD.
KW - Basophil
KW - COPD
KW - Emphysema
KW - IL-4
KW - Interstitial macrophage
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U2 - 10.1073/pnas.1813927115
DO - 10.1073/pnas.1813927115
M3 - Article
C2 - 30510003
AN - SCOPUS:85058697178
SN - 0027-8424
VL - 115
SP - 13057
EP - 13062
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 51
ER -