Journal Article

Basophils trigger emphysema development in a murine model of COPD through IL-4–mediated generation of MMP-12–producing macrophages

Miyake, Kensuke, Tateishi, Tomoya, Yoshikawa, Soichiro, Miyazaki, Yasunari, Inase, Naohiko, Yamanishi, Yoshinori, Shibata, Sho, Karasuyama, Hajime

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Air flow / Alveoli / Animal models / Animals / Asthma / Basophils - metabolism / Basophils - pathology / Biological Sciences / Cells / Cells, Cultured / Chronic obstructive pulmonary disease / Cytokines - metabolism / Differentiation / Disease Models, Animal / Elastase / Emphysema / Female / Genetic engineering / Immunology and Inflammation / Interleukin 4 / Interleukin-4 - metabolism / Leukocytes (basophilic) / Lung diseases / Lymphocytes T / Macrophages / Macrophages - metabolism / Macrophages - pathology / Macrophages, Alveolar - metabolism / Macrophages, Alveolar - pathology / Matrix metalloproteinase / Matrix Metalloproteinase 12 - physiology / Metalloproteinase / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Monocytes / Morbidity / Mortality / Neutrophils / Obstructive lung disease / Proteins / Pulmonary Disease, Chronic Obstructive - physiopathology / Pulmonary Emphysema - etiology / Pulmonary Emphysema - metabolism / Pulmonary Emphysema - pathology / Respiratory tract / Rodents