Alveolar epithelial cell chemokine expression triggered by antigen-specific cytolytic CD8+ T cell recognition

Zhao, Min; Stoler, Mark H.; Liu, Angela N.; Wei, Beiyang; Soguero, Carolina; Hahn, Young S.; Enelow, Richard I.

doi:10.1172/jci9786

Cited by 94 publications

(96 citation statements)

References 49 publications

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“…The effect of TNF-a expressed by CD8 þ T cells is mediated not exclusively by cytotoxicity, but also through the activation of alveolar target cells and their expression of inflammatory mediators. 47 Our data show elevated levels of CB in ILD-PM, correlating with the increased numbers of CD68 þ macrophages and CD8 þ T cells and elevated expression of TNF-a.…”

Section: Discussionsupporting

confidence: 59%

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

Zhang

et al. 2015

Laboratory Investigation

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Cathepsin B (CB) is involved in the turnover of proteins and has various roles in maintaining the normal metabolism of cells. In our recent study, CB is increased in the muscles of polymyositis/dermatomyositis (PM/DM). However, the role of CB in interstitial lung disease (ILD) has not been reported. ILD is a frequent complication of PM/DM, which is the leading cause of death in PM/DM. It carries high morbidity and mortality in connective tissue diseases, characterized by an overproduction of inflammatory cytokines and induced fibrosis, resulting in respiratory failure. The etiology and pathogenesis of ILD remain incompletely understood. This study investigated whether treatment with CA-074Me, a specific inhibitor of CB, attenuates ILD in PM. CB expression, inflammation, and fibrosis were analyzed in the lung tissues from patients with PM/DM. The animal model of PM was induced in guinea pigs with Coxsackie virus B1 (CVB1). CA-074Me was given 24 h after CVB1 injection for 7 consecutive days. At the end of the experiment, the animals were killed and lung tissues were collected for the following analysis. Inflammation, fibrosis and apoptosis cells, and cytokines were assessed by histological examinations and immunohistochemical analyses, western blot analysis and transferasemediated dUTP nick-end labeling assay. In patients with PM/DM, the protein levels of CB were significantly elevated in lung tissues compared with healthy controls, which correlated with increases in inflammation and fibrosis. Similarly, the expression of CB, inflammation and fibrosis, CD8 þ T cell, CD68 þ cell, tumor necrosis factor-alpha, transforming growth factor-beta1 infiltrations, and apoptotic cell death were significantly increased in lung tissues of the guinea-pig model of CVB1-induced PM. These changes were attenuated by the administration of CA-074Me. In conclusion, this study demonstrates that PM/DM increases CB expression in lung tissues and inhibition of CB reduces ILD in a guinea-pig model of CVB1-induced PM. This finding suggests that CB may be a potential therapeutic target for ILD.

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Section: Discussionsupporting

confidence: 59%

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

Zhang

et al. 2015

Laboratory Investigation

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“…Despite intensive investigation, the degree to which the antiviral and immunopathological effector mechanisms are separable remains unclear. We have previously shown that CD8 þ T-cell recognition of alveolar epithelial antigen results in severe lung inflammation, which is dependent on antigen-specific expression of TNF-a by effector T cells, triggering epithelial cell production of a variety of inflammatory mediators (11,42,45). Excessive chemokine production is known to result in inflammatory infiltration that can lead to tissue injury and organ failure (6,7,41), which we observed in our model.…”

supporting

confidence: 58%

“…Excessive chemokine production is known to result in inflammatory infiltration that can lead to tissue injury and organ failure (6,7,41), which we observed in our model. Among these chemokines, CCL2 (MCP-1) plays a particularly important role in the recruitment of inflammatory monocytes and lymphocytes, a key event in many inflammatory processes (8,34), and we have shown that its inhibition in vivo significantly abrogates CD8 þ T-cell-mediated lung injury (45). Influenza virus infection induces CCL2 expression in lung epithelial cells that directs trans-epithelial migration of monocytes (3,17).…”

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confidence: 83%

“…Abrogation of serine phosphorylation of GSK-3b and p65 by adenoviral 14.7K may be a key mechanism by which TNF-a-receptor induction of NF-kB activation and CCL2 expression are suppressed in MLE-Kd cells, and suggests that this may represent an important regulatory event in epithelial antiviral immunity. To evaluate the physiological and pathological consequences of inhibiting this aspect of epithelial TNF-receptor signaling in the setting of an effector CD8 þ T cell response to an acute virus infection, we used a well-characterized model involving intranasal influenza infection, followed by adoptive transfer of HA-specific CD8 þ effector cells (45). Transgenic animals expressing the 14.7K protein on the distal airway (alveolar and bronchiolar) epithelium under control of the surfactant protein C promoter (16) were infected and then used as recipients of activated CD8 þ T cells transferred intravenously.…”

Section: Adenovirus 147k Inhibits Cd8 þ T-cell-mediated Lung Injurymentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Srikiatkhachorn

Chintapalli

et al. 2010

Viral Immunology

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CD8þ T-cell-mediated pulmonary immunopathology in respiratory virus infection is mediated in large part by antigen-specific TNF-a expression by antiviral effector T cells, which results in epithelial chemokine expression and inflammatory infiltration of the lung. To further define the signaling events leading to lung epithelial chemokine production in response to CD8 þ T-cell antigen recognition, we expressed the adenoviral 14.7K protein, a putative inhibitor of TNF-a signaling, in the distal lung epithelium, and analyzed the functional consequences. Distal airway epithelial expression of 14.7K resulted in a significant reduction in lung injury resulting from severe influenza pneumonia. In vitro analysis demonstrated a significant reduction in the expression of an important mediator of injury, CCL2, in response to CD8 þ T-cell recognition, or to TNF-a. The inhibitory effect of 14.7K on CCL2 expression resulted from attenuation of NF-kB activity, which was independent of Ik-Ba degradation or nuclear translocation of the p65 subunit. Furthermore, epithelial 14.7K expression inhibited serine phosphorylation of Akt, GSK-3b, and the p65 subunit of NF-kB, as well as recruitment of NF-kB for DNA binding in vivo. These results provide insight into the mechanism of 14.7K inhibition of NF-kB activity, as well as further elucidate the mechanisms involved in the induction of T-cell-mediated immunopathology in respiratory virus infection.

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CXCR3‐deficiency protects influenza‐infected CCR5‐deficient mice from mortality

et al. 2008

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Mice lacking the chemokine receptor CCR5 are susceptible to mortality from a normally non-lethal influenza infection. Here we found that CXCR3-deficiency rescued CCR5-deficient (CCR5 À/À ) mice from influenza-induced mortality. The number of mononuclear phagocytes in the airways was transiently increased in CCR5 À/À mice but not in CXCR3-CCR5 double-deficient mice. Antigen-specific CXCR3-CCR5 double-deficient CD8 effector cells were less efficient at entering the airways compared with WT or CCR5 À/À CD8 effector cells. The decrease in inflammatory cell infiltrates in CXCR3-CCR5 double-deficientinfected mice correlated with a decrease in CCL2 and IFN-c production in the airways. Finally, CXCR3-CCR5 double-deficient mice that survived the primary viral challenge were protected from a lethal secondary challenge, indicating that T-cell-mediated protective memory was not compromised in mice lacking these chemokine receptors. In conclusion, CXCR3-deficiency attenuated the lethal cellular immune response in CCR5 À/À influenzainfected mice without hindering viral clearance or long-term immunity.Key words: Chemokines . Lung inflammation . T cells . Virology Supporting Information available online IntroductionInfluenza infection of the respiratory tract remains a global health burden [1]. Effective immune response, viral clearance, and recovery from respiratory viral infections, such as influenza, are partly regulated by the migration of leukocytes into inflamed tissue. Chemokines produced at sites of inflammation are among the chemoattractants that control migration of leukocytes [2].CCR5 is found on the surface of DC, macrophages, activated and memory T cells, as well as NK cells [2,3]. CCR5 ligands -CCL3 (MIP-1a), CCL4 (MIP-1b), and CCL5 (RANTES) -are commonly expressed in lungs of mice infected with respiratory viruses, including influenza [4][5][6]. CCR5-deficient (CCR5 À/À ) mice are susceptible to a fatal pneumonitis after infection with influenza [4]. It has been suggested that increased early migration of mononuclear phagocytes [4] and increased susceptibility of macrophages to apoptosis [7] contribute to the increased pulmonary inflammation that has been associated with increased mortality of CCR5 À/À mice following respiratory viral infection. However, the exact mechanism driving this increased inflammation and the participation of additional cell types in the increased morbidity of CCR5 À/À mice are not fully understood.CXCR3 is a chemokine receptor that is specific for CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (ITAC) and is expressed on 3376effector Th1 and CD8 T cells, NK cells, and NKT cells [5,6,[8][9][10][11]. CXCR3 and its ligands are expressed in a wide array of inflammatory and infectious diseases, including influenza [5,6,[8][9][10]. CXCL10 mRNA levels are increased in the lungs of CCR5 À/À mice infected with influenza compared with those of infected WT mice [4]. These findings suggest that there may be an increase in CXCR3-mediated migration of leukocytes in CCR5 À/À mice. In contrast to the increased...

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Alveolar epithelial cell chemokine expression triggered by antigen-specific cytolytic CD8+ T cell recognition

Cited by 94 publications

References 49 publications

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

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

CXCR3‐deficiency protects influenza‐infected CCR5‐deficient mice from mortality

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Alveolar epithelial cell chemokine expression triggered by antigen-specific cytolytic CD8+ T cell recognition

Cited by 94 publications

References 49 publications

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

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

CXCR3‐deficiency protects influenza‐infected CCR5‐deficient mice from mortality

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