Requirement for Tumor Necrosis Factor-Receptor 2 in Alveolar Chemokine Expression Depends upon the Form of the Ligand

Abstract

Respiratory virus infection evokes a potent T-cell response that may result in a considerable insult to the structural and functional integrity of the gas exchange units of the lung. Alveolar antigen recognition by CD8+ T lymphocytes results in significant injury that is critically dependent upon tumor necrosis factor (TNF)-alpha expressed by the CD8+ T cells and is largely dependent upon TNF-receptor 1 expression on the alveolar epithelial target cells. TNF-receptor 2 (TNF-R2)-deficient mice were used to demonstrate that CD8+ T-cell-mediated lung injury associated with clearance of experimental influenza requires TNF-R2 for full expression of immunopathology. In vitro analysis indicates that alveolar cell expression of TNF-R2 is critical in the induction of epithelial monocyte chemoattractant protein (MCP)-1 expression specifically in response to soluble TNF-alpha, suggesting an important role for this receptor in bystander lung injury. However, TNF-R2 was dispensable for induction of alveolar MCP-1 expression in response to transmembrane TNF-alpha expressed by antigen-specific CD8+ T cells, and the effects of the two receptors seem to be additive. Because TNF-R2 may be rapidly shed as part of feedback inhibition of bystander inflammation, this suggests a mechanism by which immunopathology in respiratory virus infection may be regulated and by which T-cell receptor-dependent TNF-alpha activity might bypass such negative regulation for contact-dependent antiviral activities.

Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury

“…Although AMs can produce cytokines/chemokines upon activation, non-AM cells in the lung such as alveolar epithelial cells can also produce cytokines/chemokines in response to leukocyte-released proinflammatory cytokines (8,27,47). Our results show that AM depletion dramatically downregulates cytokine/chemokine protein and mRNA expression.…”

Interference with Intraepithelial TNF-α Signaling Inhibits CD8+T-Cell-Mediated Lung Injury in Influenza Infection

“…þ T-cell expression of TNF-a and alveolar epithelial expression of TNF-R1 and TNF-R2 on lung epithelial cells are required for significant T-cell-mediated lung injury (24,43), and that induction of epithelial chemokine expression, particularly CCL2, is a primary contributor to the immunopathology (37,45). In this study, we found that distal airway epithelial CCL2 induction was abrogated by adenoviral 14.7K through the inhibition of TNF-a-receptorinduced GSK-3b phosphorylation and recruitment of NF-kB to the CCL2 promoter.…”

“…The enhanced inflammatory response and leukocyte recruitment occurring after infection with highly pathogenic strains of influenza has been suggested to be dependent on TNF-and i-NOS-producing dendritic cells, as well as the CCR2 receptor (1,23). Epithelial CCL2 is rapidly induced in response to CD8 þ T-cell recognition in vitro and in vivo (32,43,45), and appears to require both TNF receptors, TNF-R1 and TNF-R2 (24).…”

Cigarette smoke selectively enhances viral PAMP– and virus-induced pulmonary innate immune and remodeling responses in mice

“…After 2 weeks of CS exposure, the mice were lightly anesthetized and 5.0 × 10 3.375 TCID50 (50% tissue culture infective doses) of A/PR8/34 influenza (equivalent to 0.05 LD50 in C57BL/6J mice) was administered via nasal aspiration in 50 μl of serumfree medium, using techniques previously described by our laboratories (51). The mice were then sacrificed at postinfection days 3, 6, 9, 12, and 15.…”