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

Significance Chronic obstructive pulmonary disease has generally been considered a non-Th2-type lung disease, in contrast to allergic asthma. We identified unexpected roles for basophils, Th2 cytokine IL-4, and interstitial macrophages in triggering emphysema formation in spite of the fact that basophils account for less than 1% of cellular infiltrates in the lung. Our observations in a series of genetically engineered mice illustrated that basophil-derived IL-4 acts on lung-infiltrating monocytes to promote their differentiation into interstitial macrophages that in turn produce a pathogenic enzyme, matrix metalloproteinase-12 (MMP-12), resulting in the destruction of alveolar walls and leading to emphysema. Thus, the present study has identified a previously unappreciated role for the basophil-derived IL-4/monocyte–derived interstitial macrophage/MMP-12 axis at the initiation phase of emphysema development in mice. 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.