IFN Regulatory Factor 3 Contributes to the Host Response during <i>Pseudomonas aeruginosa</i> Lung Infection in Mice

Carrigan, Svetlana O.; Junkins, Robert D.; Yang, Yong; MacNeil, Adam J.; Richardson, Christopher T.; Johnston, Brent; Lin, Tong‐Jun

doi:10.4049/jimmunol.0903429

Cited by 51 publications

(45 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With the exception of limited dependency upon CD14, P. aeruginosa stimulated a TLR4/TRIF/MD2/TANK binding kinase I-dependent induction of IFN-b. This result is consistent with the involvement of TRIF and IRF3 in the clearance of P. aeruginosa from the lung, as previously reported (18,43). Although we did not identify other components of P. aeruginosa that might induce the expression of IFN-b, the type III secretion system was not involved, because mutants in various type III secretion system effectors were not impaired during the induction of IFN-b (data not shown).…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Induction of Type I Interferon Signaling by Pseudomonas aeruginosa Is Diminished in Cystic Fibrosis Epithelial Cells

Parker

Cohen

Alhede

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

The clinical manifestations of infection in cystic fibrosis (CF) are restricted to the lung, and involve a limited number of pathogens, suggesting a specific defect in mucosal immunity. We postulated that cystic fibrosis transmembrane conductance regulator (CTFR) mutations could affect the activation of type I interferon signaling in airway epithelial cells, which function in immune surveillance and initiate the recruitment and activation of immune cells. In response to infection with Pseudomonas aeruginosa, Ifnb was induced more than 100-fold in the murine lung, and the phosphorylation of STAT1 was similarly induced by the expected TLR4/TRIF/MD2/TBK1 cascade. The stimulation by P. aeruginosa of CF (IB3) cells and control (C-38) human cell lines similarly resulted in the induction of IFN-b, but to a significantly lower extent in CF airway cells. The potential consequences of diminished type I IFN signaling were demonstrated in a murine model of P. aeruginosa pneumonia, pretreatment with polyinosinic:polycytidylic acid significantly enhanced bacterial clearance and correlated with increased numbers of mature CD11c 1 / CD86 1 dendritic cells (DCs) in the lung. Using culture supernatants from CF or control cell lines stimulated with P. aeruginosa, we similarly demonstrated the diminished activation of human monocytederived DCs by incubation with CF compared with normal epithelial cell culture supernatants, which was dependent on IFN-b. These observations suggest that dysfunction of the CFTR in airway epithelial cells may contribute to impaired immune surveillance in the CF airway and resultant colonization by P. aeruginosa.

show abstract

Section: Discussionsupporting

confidence: 93%

“…Studies of TRIF and IRF3 knockout mice showed a decreased ability to clear infections (18,43). Accordingly, we used a gainof-function model to determine if enhanced type I IFN signaling might facilitate the clearance of P. aeruginosa.…”

Section: Effects Of Type I Ifn Signaling On P Aeruginosa Clearance Fmentioning

confidence: 99%

Induction of Type I Interferon Signaling by Pseudomonas aeruginosa Is Diminished in Cystic Fibrosis Epithelial Cells

Parker

Cohen

Alhede

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…However, no differences in activity were observed in the BALF at this time point. These data stand in stark contrast to previous results in other gene knockout mice we and others have generated using this P. aeruginosa lung infection model, in which increased bacterial burden is usually associated with increased mortality (49,55,56). Altogether, these data suggest that the increased mortality in RCAN1-deficient animals may not be directly caused by bacterial pneumonia.…”

Section: Statisticscontrasting

confidence: 98%

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Junkins

MacNeil

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Respiratory tract infection with Pseudomonas aeruginosa is a common cause of hospitalization in immune-compromised individuals. However, the molecular mechanisms involved in the immune response to P. aeruginosa lung infection remain incompletely defined. In this study, we demonstrate that the regulator of calcineurin 1 (RCAN1) is a central negative regulator of inflammation in a mouse model of acute bacterial pneumonia using the opportunistic bacterial pathogen P. aeruginosa. RCAN1-deficient mice display greatly increased mortality following P. aeruginosa lung infection despite enhanced neutrophil recruitment and bacterial clearance. This mortality is associated with higher systemic levels of proinflammatory cytokines in RCAN1-deficient animals. These aberrant inflammatory responses coincide with increased transcriptional activity of proinflammatory RCAN1-target proteins NFAT and NF-κB. In addition, we reveal a novel regulatory role for RCAN1 in the ERK/STAT3 pathway both in vitro and in vivo, suggesting that aberrant STAT3 activity may significantly contribute to delayed resolution of inflammatory responses in our model. Together, these findings demonstrate that RCAN1 is a potent negative regulator of inflammation during respiratory tract infections.

show abstract

“…2C). As TLR7 mediated induction of CCL5, but not TNFα mRNA was impaired in TRAM deficient cells, this indicated that TRAM was leveraging TLR7 signaling not via NF-κB, but perhaps via the IRF pathway and thus may also affect transcription of the IFN-β gene [6], [21]. Hence, the role of TRAM in the transcriptional regulation of IFN-β was also examined wherein it was found that suppression of TRAM expression resulted in a significant decrease in R848 and LPS, but not Poly(I:C) mediated IFN-β induction when compared to control cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

The TIR-Domain Containing Adaptor TRAM Is Required for TLR7 Mediated RANTES Production

Shevlin

Miggin

2014

PLoS ONE

View full text Add to dashboard Cite

Toll-like receptor 7 (TLR7) plays a vital role in the immune response to ssRNA viruses such as human rhinovirus (HRV) and Influenza, against which there are currently no treatments or vaccines with long term efficacy available. Clearly, a more comprehensive understanding of the TLR7 signaling axis will contribute to its molecular targeting. TRIF related adaptor molecule (TRAM) plays a vital role in TLR4 signaling by recruiting TRIF to TLR4, followed by endosomal trafficking of the complex and initiation of IRF3 dependent type I interferon production as well as NF-κB dependent pro-inflammatory cytokine production. Towards understanding the molecular mechanisms that regulate TLR7 functionality, we found that TRAM−/− murine macrophages exhibited a transcriptional and translational impairment in TLR7 mediated RANTES, but not TNFα, production. Suppression of TRAM expression in human macrophages also resulted in an impairment in TLR7 mediated CCL5 and IFN-β, but not TNFα, gene induction. Furthermore, suppression of endogenous human TRAM expression in human macrophages significantly impaired RV16 induced CCL5 and IFNβ, but not TNFα gene induction. Additionally, TRAM-G2A dose-dependently inhibited TLR7 mediated activation of CCL5, IFNβ and IFNα reporter genes. TLR7-mediated phosphorylation and nuclear translocation of IRF3 was impaired in TRAM−/− cells. Finally, co-immunoprecipitation studies indicated that TRAM physically interacts with MyD88 upon TLR7 stimulation, but not under basal conditions. Our results clearly demonstrate that TRAM plays a, hitherto unappreciated, role in TLR7 signaling through a novel signaling axis containing, but not limited to, MyD88, TRAM and IRF3 towards the activation of anti-viral immunity.

show abstract

IFN Regulatory Factor 3 Contributes to the Host Response during Pseudomonas aeruginosa Lung Infection in Mice

Abstract: Material

Cited by 51 publications

References 32 publications

Induction of Type I Interferon Signaling by Pseudomonas aeruginosa Is Diminished in Cystic Fibrosis Epithelial Cells

Induction of Type I Interferon Signaling by Pseudomonas aeruginosa Is Diminished in Cystic Fibrosis Epithelial Cells

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

The TIR-Domain Containing Adaptor TRAM Is Required for TLR7 Mediated RANTES Production

Contact Info

Product

Resources

About