CXC Chemokine Receptor CXCR2 Is Essential for Protective Innate Host Response in Murine<i>Pseudomonas aeruginosa</i>Pneumonia

Tsai, Wan C.; Strieter, Robert M.; Mehrad, Borna; Newstead, Michael W.; Zeng, Xianying; Standiford, Theodore J.

doi:10.1128/iai.68.7.4289-4296.2000

Cited by 253 publications

(234 citation statements)

References 47 publications

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“…During acute pulmonary inflammation, the CXC chemokines KC, MIP-2, and LIX generate the chemotactic gradients that direct neutrophils from the vascular to the alveolar spaces (30,31,33,46). IL-6 is also expressed in the lungs and is required for maximal neutrophil recruitment and bacterial killing (25,47).…”

Section: Discussionmentioning

confidence: 99%

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Quinton

Jones

Simms

et al. 2007

The Journal of Immunology

122

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Eradication of bacteria in the lower respiratory tract depends on the coordinated expression of proinflammatory cytokines and consequent neutrophilic inflammation. To determine the roles of the NF-κB subunit RelA in facilitating these events, we infected RelA-deficient mice (generated on a TNFR1-deficient background) with Streptococcus pneumoniae. RelA deficiency decreased cytokine expression, alveolar neutrophil emigration, and lung bacterial killing. S. pneumoniae killing was also diminished in the lungs of mice expressing a dominant-negative form of IκBα in airway epithelial cells, implicating this cell type as an important locus of NF-κB activation during pneumonia. To study mechanisms of epithelial RelA activation, we stimulated a murine alveolar epithelial cell line (MLE-15) with bronchoalveolar lavage fluid (BALF) harvested from mice infected with S. pneumoniae. Pneumonic BALF, but not S. pneumoniae, induced degradation of IκBα and IκBβ and rapid nuclear accumulation of RelA. Moreover, BALF-induced RelA activity was completely abolished following combined but not individual neutralization of TNF and IL-1 signaling, suggesting either cytokine is sufficient and necessary for alveolar epithelial RelA activation during pneumonia. Our results demonstrate that RelA is essential for the host defense response to pneumococcus in the lungs and that RelA in airway epithelial cells is primarily activated by TNF and IL-1.

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Section: Discussionmentioning

confidence: 99%

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Quinton

Jones

Simms

et al. 2007

The Journal of Immunology

122

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“…Recruitment of leukocytes in response to P. aeruginosa peaks at 12-24 h postinfection (18). The AM is vital in the initial host response to pulmonary infections (24 -26), and together with neutrophils that are recruited to the lungs, AMs mediate the phagocytic response to Gram-negative bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…Data are from one experiment that is representative of three independent experiments. P. aeruginosa infection (18). We examined pulmonary leukocyte recruitment by enumerating total and differential pulmonary leukocyte counts 24 h after inoculation with saline or P. aeruginosa to determine whether the increased susceptibility after BMT could be explained on this basis (Fig.…”

Section: Pulmonary Leukocyte Recruitment In Response To P Aeruginosamentioning

confidence: 99%

Defective Phagocytosis and Clearance of Pseudomonas aeruginosa in the Lung Following Bone Marrow Transplantation

Ojielo

Cooke²,

Mancuso

et al. 2003

The Journal of Immunology

Self Cite

126

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Bone marrow transplantation (BMT) is an important therapeutic option for a variety of malignant and nonmalignant disorders. Unfortunately, BMT recipients are at increased risk of infection, and in particular, pulmonary complications occur frequently. Although the risk of infection is greatest during the neutropenic period immediately following transplant, patients are still vulnerable to pulmonary infections even after neutrophil engraftment. We evaluated the risk of infection in this postengraftment period by using a well-established mouse BMT model. Seven days after syngeneic BMT, B6D2F1 mice are no longer neutropenic, and by 3 wk, they demonstrate complete reconstitution of the peripheral blood. However, these mice remain more susceptible throughout 8 wk to infection after intratracheal administration of Pseudomonas aeruginosa; increased mortality in the P. aeruginosa-infected BMT mice correlates with increased bacterial burden in the lungs as well as increased systemic dissemination. This heightened susceptibility to infection was not secondary to a defect in inflammatory cell recruitment to the lung. The inability to clear P. aeruginosa in the lung correlated with reduced phagocytosis of the bacteria by alveolar macrophages (AMs), but not neutrophils, decreased production of TNF-α by AMs, and decreased levels of TNF-α and IFN-γ in the bronchoalveolar lavage fluid following infection. Expression of the β2 integrins CD11a and CD11c was reduced on AMs from BMT mice compared with wild-type mice. Thus, despite restoration of peripheral blood count, phagocytic defects in the AMs of BMT mice persist and may contribute to the increased risk of infection seen in the postengraftment period.

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“…Lungs were removed from euthanized animals and leukocytes prepared as previously described (26). Briefly, lungs were minced with scissors to fine slurry in 15 ml of digestion buffer (RPMI, 10% fetal calf serum, 1 mg/ml collagenase [Roche Diagnostics], 30 μg/ml DNase [Sigma-Aldrich]) per lung.…”

Section: Methodsmentioning

confidence: 99%

“…P. aeruginosa challenge in septic WT and IRAK-M -/-mice. Previous work from our laboratory has identified the importance of inflammatory cytokines and chemokines (e.g., TNF-α, IL-12, and the CXC chemokines macrophage inflammatory protein-2 [MIP-2] and IFN-γ-inducible protein 10 [IP-10]) to the innate immune response against bacterial pathogens in the lung (12)(13)(14)(15)(26)(27)(28)(29)(30)(31). We therefore examined…”

Section: Bacterial Clearance Following It P Aeruginosa Administratmentioning

confidence: 99%

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Deng

Cheng

Newstead

et al. 2006

Journal of Clinical Investigation

166

243

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Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonas aeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M -/-animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M -/-animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.

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CXC Chemokine Receptor CXCR2 Is Essential for Protective Innate Host Response in MurinePseudomonas aeruginosaPneumonia

Abstract: Pulmonary infection due to

Cited by 253 publications

References 47 publications

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Defective Phagocytosis and Clearance of Pseudomonas aeruginosa in the Lung Following Bone Marrow Transplantation

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

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