RETRACTED: Induction of a Homeostatic Circuit in Lung Tissue by Microbial Compounds

This article has been retracted at the request of the inhouse Editor, Peter Lee, and the authors. The text below has been agreed between Peter Lee and the corresponding author. Please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).Reason: The authors discovered that a duplication of several gel images occurred during the preparation of the above manuscript. Specifically, the gel images in Figure 2A were duplicated within Figure 2A, and in Figures 5F and 6B. These figures are important in showing the amount of Smad 2/3 as an indicator of alveolar macrophage-epithelial cell interactions, which explains the mechanism of the proposed homeostatic circuit in the lungs, and thus we are retracting the manuscript. The authors stand by the validity of the other figures, and sincerely apologize for the inconvenience caused by this retraction

Inhibition of T Cells Provides Protection against Early Invasive Pneumococcal Disease ▿ †

Infections caused by Streptococcus pneumoniae are major causes of morbidity and mortality, which are in part mediated by immune cell-dependent mechanisms. Yet, the specific contributions of individual cell types to immunopathology are only partially understood. T cells are well characterized with respect to their function in protective humoral immune responses; however, their roles during early stages of infection and invasive pneumococcal disease (IPD) are less well defined. Using a mouse model of pneumococcal sepsis, we found that CD4+ T cells were recruited to the lung as early as 12 h after intranasal infection. Recruitment was accompanied by upregulation of CD69 and B7-H1, reflecting T-cell activation. Unexpectedly, major histocompatibility complex (MHC) class II-deficient mice, which lack CD4+ T cells, displayed an increased survival despite comparable bacterial titers in the blood, spleen, and lung. The higher survival correlated with a lower cytokine and chemokine response upon S. pneumoniae challenge in MHC class II-deficient mice, suggesting that inflammation may contribute to the mortality of IPD. Comparable to the case for MHC class II-deficient mice, antibody-mediated depletion of CD4+ T cells and drug-induced inhibition of T-cell function with cyclosporine, or interference with T-cell activation using CTLA4-immunoglobulin (Abatacept), led to significant increases in survival during IPD. Our results reveal an important and adverse role of CD4+ T cells in the pathogenesis of IPD and suggest that modulation of T-cell activation during early phases of S. pneumoniae invasive infection may provide a therapeutic option

Type I Interferon Protects against Pneumococcal Invasive Disease by Inhibiting Bacterial Transmigration across the Lung

<div><p><i>Streptococcus pneumoniae</i> infection is a leading cause of bacterial pneumonia, sepsis and meningitis and is associated with high morbidity and mortality. Type I interferon (IFN-I), whose contribution to antiviral and intracellular bacterial immunity is well established, is also elicited during pneumococcal infection, yet its functional significance is not well defined. Here, we show that IFN-I plays an important role in the host defense against pneumococci by counteracting the transmigration of bacteria from the lung to the blood. Mice that lack the type I interferon receptor (<i>Ifnar1</i>^−/−) or mice that were treated with a neutralizing antibody against the type I interferon receptor, exhibited enhanced development of bacteremia following intranasal pneumococcal infection, while maintaining comparable bacterial numbers in the lung. In turn, treatment of mice with IFNβ or IFN-I-inducing synthetic double stranded RNA (poly(I:C)), dramatically reduced the development of bacteremia following intranasal infection with <i>S. pneumoniae</i>. IFNβ treatment led to upregulation of tight junction proteins and downregulation of the pneumococcal uptake receptor, platelet activating factor receptor (PAF receptor). In accordance with these findings, IFN-I reduced pneumococcal cell invasion and transmigration across epithelial and endothelial layers, and <i>Ifnar1</i>^−/− mice showed overall enhanced lung permeability. As such, our data identify IFN-I as an important component of the host immune defense that regulates two possible mechanisms involved in pneumococcal invasion, i.e. PAF receptor-mediated transcytosis and tight junction-dependent pericellular migration, ultimately limiting progression from a site-restricted lung infection to invasive, lethal disease.</p></div

IFNβ reduces PAF receptor levels on lung epithelial and endothelial cell lines and in the lung.

<p>(A) A549 cells were stimulated with 1000 U/ml IFNβ, or an equal volume of PBS, for 8 h and PAF receptor mRNA levels were determined by Q-PCR (normalized to <i>β-ACTIN</i> expression), n = 9. (B) A549 cells were incubated with or without 1000 U/ml IFNβ, 10 ng/ml TNFα or both IFNβ and TNFα for 8 h and expression levels of <i>PAFR</i> and <i>NFKBIA</i> were determined by Q-PCR (normalized to <i>β-ACTIN</i> expression). n = 7–8. Statistical analysis was performed with the Mann-Whitney test. * P<0.05, ** P<0.01. Data shown are representative of three experiments. (C) rBCEC₆ cells were stimulated with or without 10 ng/ml TNFα or TNFα in combination with 1000 U/ml IFNβ for 24 hours. Total lysates were analyzed by immuno-blotting using antibodies against PAF receptor and β-ACTIN. Relative protein expression levels were quantified by Image Studio Lite software. (D) C57BL/6 mice were treated i.n. with recombinant mouse IFNβ and euthanized after 24 hours. PAF receptor mRNA levels were determined by Q-PCR (normalized to cyclophilin expression). Bars represent median value, n = 4–8, ** P<0.01. (E) A549 cells were incubated with 1000 U/ml recombinant IFNβ or PBS for 20 hours and PAF receptor antagonist CV3988 or vehicle control for 30 minutes prior to performing an invasion assay with R6. Data from three independent experiments are combined. n = 12. Bars indicate mean ± SEM. * P<0.05 (Mann Whitney test).</p

Pre-treatment of mice with IFNβ protects against the development of invasive disease.

<p>(A–B) 6 week old C57BL/6J mice were pretreated with recombinant mouse IFNβ, poly(I:C) or PBS (Ctrl) i.n. 24 hours before intranasal infection with 5×10⁶ CFU D39X. (A) Blood CFU titers were determined at various time points and analyzed using the Mann-Whitney test. Bars represent median, n = 14. Dashed line indicates the limit of detection. (B) Survival of mice was analyzed using the Log-Rank test. n = 14. For all graphs, ** P<0.01, *** P<0.005, **** P<0.001.</p