Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand

Abstract

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.

Distinct Macrophage Subpopulations Characterize Acute Infection and Chronic Inflammatory Lung Disease

“…In contrast, infection with high-fatality influenza A strains (i.e., avian H5N1/97) leads to patient death from acute respiratory distress and multiple organ dysfunction, postulated to be caused by aberrant cytokine production from virus-exposed lung MFs (5,35). Interestingly, CCR2 2/2 mice infected with the highly virulent PR8 influenza A strain virus have decreased lung monocyte recruitment and are protected against morbidity and mortality independent of virus clearance efficiency (6,14), clearly highlighting the significant contributions of lung monocytes in acute lung disease. In our model of nonlethal influenza infection, we observed the highest levels of iNOS and IL-6, but also Arg I and IL-10, in subpopulation Mv.…”

“…Cell turnover rate is slow (11) and is maintained by constitutively immigrating CCR2 2 Gr-1 2 resident monocytes (12,13). In contrast, CCR2 + Gr-1 + inflammatory monocytes rapidly migrate into alveolar airspaces after lung infection and are believed to be the main effectors of acute lung injury and infection-related mortality (6,14,15). Increased AMFs, however, are correlated with the severity of chronic obstructive pulmonary disease (COPD) (16), a debilitating chronic condition characterized by progressive irreversible airflow limitation and lung parenchyma destruction.…”

“…Because there is complex overlap between tissue homeostasis, inflammation, and disease pathogenesis, it is now thought that distinct MF subpopulations may exist that subserve their protective or pathogenic roles (1). A prime example may be in lungs, where residential alveolar MFs (AMFs) are simultaneously implicated to play many homeostatic (4), proinflammatory (5,6), and pathogenic roles (7,8).…”

Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection

“…A strong induction of chemokines and cytokines was also observed in mice infected with the high pathogenic 1918 virus [8,9] and the H5N1 virus [30,31] and were associated with unfavorable disease outcome [4,32]. Particularly, the expression of Ccl2 by alveolar cells, the activation of its receptor on macrophages and their subsequent recruitment to the lung has been shown to cause detrimental immunepathology [33,34]. Ccr2 mutant mice showed less severe lung leakage and increased survival after influenza A infections [34].…”

“…Particularly, the expression of Ccl2 by alveolar cells, the activation of its receptor on macrophages and their subsequent recruitment to the lung has been shown to cause detrimental immunepathology [33,34]. Ccr2 mutant mice showed less severe lung leakage and increased survival after influenza A infections [34]. On the other hand, mouse mutants deficient in the Ccr5 receptor which is also expressed on macrophages, showed increased lethality from influenza A infections [35].…”