Mononuclear phagocytes have been attributed a crucial role in the host defense toward infl uenza virus (IV), but their contribution to infl uenza-induced lung failure is incompletely understood. We demonstrate for the fi rst time that lung-recruited " exudate " macrophages signifi cantly contribute to alveolar epithelial cell (AEC) apoptosis by the release of tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) in a murine model of infl uenzainduced pneumonia. Using CC-chemokine receptor 2 -defi cient (CCR2 ؊ / ؊ ) mice characterized by defective infl ammatory macrophage recruitment, and blocking anti-CCR2 antibodies, we show that exudate macrophage accumulation in the lungs of infl uenzainfected mice is associated with pronounced AEC apoptosis and increased lung leakage and mortality. Among several proapoptotic mediators analyzed, TRAIL messenger RNA was found to be markedly up-regulated in alveolar exudate macrophages as compared with peripheral blood monocytes. Moreover, among the different alveolar-recruited leukocyte subsets, TRAIL protein was predominantly expressed on macrophages. Finally, abrogation of TRAIL signaling in exudate macrophages resulted in signifi cantly reduced AEC apoptosis, attenuated lung leakage, and increased survival upon IV infection. Collectively, these fi ndings demonstrate a key role for exudate macrophages in the induction of alveolar leakage and mortality in IV pneumonia. Epithelial cell apoptosis induced by TRAIL-expressing macrophages is identifi ed as a major underlying mechanism.

Influenza A virus pneumonia is characterized by severe lung injury and high mortality. Early infection elicits a strong recruitment of monocytes from the peripheral blood across the endo-/epithelial barrier into the alveolar air space. However, it is currently unclear which of the infected resident lung cell populations, alveolar epithelial cells or alveolar macrophages, elicit monocyte recruitment during influenza A virus infection. In the current study, we investigated whether influenza A virus infection of primary alveolar epithelial cells and resident alveolar macrophages would elicit a basal-to-apical monocyte transepithelial migration in vitro. We found that infection of alveolar epithelial cells with the mouse-adapted influenza A virus strain PR/8 strongly induced the release of monocyte chemoattractants CCL2 and CCL5 followed by a strong monocyte transepithelial migration, and this monocytic response was strictly dependent on monocyte CCR2 but not CCR5 chemokine receptor expression. Analysis of the adhesion molecule pathways demonstrated a role of ICAM-1, VCAM-1, integrin-associated protein (CD47), and junctional adhesion molecule-c on the epithelial cell surface interacting with monocyte β1 and β2 integrins and integrin-associated protein in the monocyte transmigration process. Importantly, addition of influenza A virus-infected alveolar macrophages further enhanced monocyte transmigration across virus-infected epithelium in a TNF-α-dependent manner. Collectively, the data show an active role for virus-infected alveolar epithelium in the regulation of CCL2/CCR2-dependent monocyte transepithelial migration during influenza infection that is essentially dependent on both classical β1 and β2 integrins but also junctional adhesion molecule pathways.

We conclude that recruited lung macrophages attenuate IL-1β-mediated acute lung injury in gram-negative pneumonia by release of IL-1ra.

Lung DCs actively participate in the early inflammatory response to both inhaled bacterial toxins and live bacteria and play a yet unrecognized role in regulating lung barrier integrity.

No abstract