Abstract
Neutrophil migration into the airways is an important process to fight infection and is mediated by cell adhesion molecules. The intercellular adhesion molecules, ICAM-1 (CD54) and ICAM-2 (CD102) are known ligands for the neutrophil integrins, lymphocyte function associated antigen (LFA)-1 (αLβ2; CD11a/CD18), and macrophage-1 antigen (Mac-1;αMβ2;CD11b/CD18) and are implicated in leukocyte migration into the lung. However, it is ill-defined how neutrophils exit the lung and the role for ICAMs in trans-epithelial migration (TEpM) across the bronchial or alveolar epithelium. We found that human and murine alveolar epithelium expressed ICAM-1, whilst the bronchial epithelium expressed ICAM-2, and both were up-regulated during inflammatory stimulation in vitro and in inflammatory lung diseases such as cystic fibrosis. Although β2 integrins interacting with ICAM-1 and -2 mediated neutrophil migration across human bronchial epithelium in vitro, neither ICAM-2 nor LFA-1 binding of ICAM-1 mediated murine neutrophil migration into the lung or broncho-alveolar space during LPS-induced inflammation in vivo. Furthermore, TEpM of neutrophils themselves resulted in increased epithelial junctional permeability and reduced barrier function in vitro. This suggests that although β2 integrins interacting with ICAMs may regulate low levels of neutrophil traffic in healthy lung or early in inflammation when the epithelial barrier is intact; these interactions may be redundant later in inflammation when epithelial junctions are disrupted and no longer limit TEpM.
Highlights
Neutrophilic inflammation underlies many chronic lung diseases including cystic fibrosis (CF), bronchiectasis, and chronic obstructive pulmonary disease (COPD) [1, 2]
intercellular adhesion molecules (ICAMs)-2 was strongly expressed on the bronchial epithelium and weakly on the alveolar epithelium (Figure 1A), indicating that ICAM-1 and ICAM-2 are differentially expressed on healthy adult human lung epithelium
Only modestly increased levels of ICAM-1 and ICAM-2 expression were found on inflamed bronchial epithelium from patients with COPD compared to normal lung (Figure 1B)
Summary
Neutrophilic inflammation underlies many chronic lung diseases including cystic fibrosis (CF), bronchiectasis, and chronic obstructive pulmonary disease (COPD) [1, 2]. The movement of leukocytes such as neutrophils from the blood across the endothelium is a highlyorganized process, consisting of well characterized steps of capture, rolling, arrest, adhesion, crawling and transmigration of leukocytes across the blood vessel wall [3]. Each of these steps is mediated via interactions between cell adhesion molecules expressed by leukocytes and endothelial cells, such as integrins, selectins, intercellular adhesion molecules (ICAMs) and junctional adhesion molecules (JAMs) [4]. Different mechanisms may occur to mediate leukocyte migration into the lung in response to inflammation or infection
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