β1 Integrin regulates adult lung alveolar epithelial cell inflammation.

Erin J Plosa,Timothy S Blackwell,Seunghyi Kook,Lisa R Young,Roy Zent,Wei Han,Susan H Guttentag,Ambra Pozzi,Scott M Haake,Jennifer M Sucre,Peter M Gulleman,Vasiliy V Polosukhin,Linda A Gleaves,John T Benjamin

doi:10.1172/jci.insight.129259

Erin J Plosa, Timothy S Blackwell + Show 12 more

Open Access

https://doi.org/10.1172/jci.insight.129259

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Abstract

Integrins, the extracellular matrix receptors that facilitate cell adhesion and migration, are necessary for organ morphogenesis; however, their role in maintaining adult tissue homeostasis is poorly understood. To define the functional importance of β1 integrin in adult mouse lung, we deleted it after completion of development in type 2 alveolar epithelial cells (AECs). Aged β1 integrin-deficient mice exhibited chronic obstructive pulmonary disease-like (COPD-like) pathology characterized by emphysema, lymphoid aggregates, and increased macrophage infiltration. These histopathological abnormalities were preceded by β1 integrin-deficient AEC dysfunction such as excessive ROS production and upregulation of NF-κB-dependent chemokines, including CCL2. Genetic deletion of the CCL2 receptor, Ccr2, in mice with β1 integrin-deficient type 2 AECs impaired recruitment of monocyte-derived macrophages and resulted in accelerated inflammation and severe premature emphysematous destruction. The lungs exhibited reduced AEC efferocytosis and excessive numbers of inflamed type 2 AECs, demonstrating the requirement for recruited monocytes/macrophages in limiting lung injury and remodeling in the setting of a chronically inflamed epithelium. These studies support a critical role for β1 integrin in alveolar homeostasis in the adult lung.

Highlights

Integrins are heterodimeric transmembrane receptors consisting of α and β subunits that bind extracellular matrix (ECM) components; propagate bidirectional signaling [1,2,3,4,5]; and regulate critical processes such as adhesion, migration and proliferation that are required for the development of multicellular organisms [6,7,8,9,10]
Promoter. β1 Integrin deletion was induced in type 2 alveolar epithelial cells (AECs) by addition of dox to drinking water from day P28, at the completion of lung development, until 2 months of age
We found that 68% ± 4% of monocytes/macrophages collected from β1rtTA lungs contained pro–surfactant protein C (SP-C)+ material compared with 14% ± 2% of these cells from β1f/f lungs (Figure 7, C and D)

Summary

Introduction

Integrins are heterodimeric transmembrane receptors consisting of α and β subunits that bind extracellular matrix (ECM) components; propagate bidirectional signaling [1,2,3,4,5]; and regulate critical processes such as adhesion, migration and proliferation that are required for the development of multicellular organisms [6,7,8,9,10]. Β1 Integrins are present in epithelial cells, where they mediate cell adhesion to basement membranes and facilitate epithelial tissue organogenesis [9, 11,12,13,14,15,16,17,18,19,20,21,22,23,24]. Macrophage depletion rescued the alveolarization defect in these mice [22] These findings suggest that epithelial β1 integrin dysfunction has deleterious consequences in lung epithelium through regulation of innate immunity. The mechanisms whereby these epithelial-macrophage interactions occur are uncertain, and, perhaps more importantly, the function of β1 integrin in the adult lung is not established

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