The Role of Interferon‐γ in Murine Pneumococcal Pneumonia

Self Cite

100

To determine the role of endogenous IL-18 during pneumonia, IL-18 gene-deficient (IL-18−/−) mice and wild-type (WT) mice were intranasally inoculated with Streptococcus pneumoniae, the most common causative agent of community-acquired pneumonia. Infection with S. pneumoniae increased the expression of IL-18 mRNA and was associated with elevated concentrations of both precursor and mature IL-18 protein within the lungs. IL-18−/− mice had significantly more bacteria in their lungs and were more susceptible for progressing to systemic infection at 24 and 48 h postinoculation. Similarly, treatment of WT mice with anti-IL-18 was associated with enhanced outgrowth of pneumococci. In contrast, the clearance of pneumococci from lungs of IL-12−/− mice was unaltered when compared with WT mice. Furthermore, anti-IL-12 did not influence bacterial clearance in either IL-18−/− or WT mice. These data suggest that endogenous IL-18, but not IL-12, plays an important role in the early antibacterial host response during pneumococcal pneumonia.

Section: Discussionmentioning

confidence: 86%

IL-18 Improves the Early Antimicrobial Host Response to Pneumococcal Pneumonia

Lauw

Branger

Florquin

et al. 2002

Self Cite

100

“…For example, the ELR-positive CXC chemokine LIX and the CC chemokine MCP-1 each facilitate neutrophil recruitment in the lungs (30,31). In addition, IL-17 and IFN-␥ are T cell-derived cytokines that can augment neutrophil recruitment to bacteria in the lungs (32)(33)(34)(35)(36). The concentrations of these four cytokines were measured in WT and TM mice with pneumococcal pneumonia (Table I).…”

Section: Chemokine Expressionmentioning

confidence: 99%

Lung NF-κB Activation and Neutrophil Recruitment Require IL-1 and TNF Receptor Signaling during Pneumococcal Pneumonia

Jones

Simms

Lupa

et al. 2005

143

126

Pulmonary inflammation is an essential component of the host defense against Streptococcus pneumoniae infection of the lungs. The early response cytokines, TNF-α and IL-1, are rapidly induced upon microbial exposure. Mice deficient in all TNF- and IL-1-dependent signaling receptors were used to determine the roles of these cytokines during pneumococcal pneumonia. The deficiency of signaling receptors for TNF and IL-1 decreased bacterial clearance. Neutrophil recruitment to alveolar air spaces was impaired by receptor deficiency, as was pulmonary expression of the neutrophil chemokines KC and MIP-2. Because NF-κB mediates the expression of both chemokines, we assessed NF-κB activation in the lungs. During pneumococcal pneumonia, NF-κB proteins translocate to the nucleus and activate gene expression; these functions were largely abrogated by the deficiency of receptors for TNF-α and IL-1. Thus, the combined deficiency of TNF and IL-1 signaling reduces innate immune responses to S. pneumoniae in the lungs, probably due to essential roles for these receptors in activating NF-κB.

“…More recently, it was shown that S. pneumoniae may also be recognized by inflammasomes that are dependent upon the adaptor molecule ASC (16)(17)(18)(19). Together, these pathways initiate immune activation and lead to production of inflammatory cytokines and chemokines that subsequently mediate the recruitment of leukocytes to the site of infection (20)(21)(22)(23)(24)(25)(26). However, when this occurs within the brain, the ensuing inflammatory response is argued to ultimately cause neuronal damage and/ or death (9,10).…”

mentioning

confidence: 99%

“…In patients with S. pneumoniae sepsis, plasma IFN-g levels were reported to be elevated, and circulating levels of the cytokine correlated with mortality (44). In murine models, IFN-g inhibition/ ablation was reported to lead to decreased survival (25,26,45) or to have no effect on mortality (23,46). Furthermore, in the absence of IFN-g, decreased levels of chemokines involved in neutrophil recruitment, as well as neutrophils themselves, were reported by some groups (23,26), and this was associated with a lower bacterial load (23).…”

mentioning

confidence: 99%

“…In murine models, IFN-g inhibition/ ablation was reported to lead to decreased survival (25,26,45) or to have no effect on mortality (23,46). Furthermore, in the absence of IFN-g, decreased levels of chemokines involved in neutrophil recruitment, as well as neutrophils themselves, were reported by some groups (23,26), and this was associated with a lower bacterial load (23). More recently, and in contrast, IFN-g-deficient mice were argued to have higher levels of neutrophils and chemokines associated with their recruitment, as well as increased bacterial load (25).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

Mitchell

Yau

McQuillan

et al. 2012

The pathology associated with Streptococcus pneumoniae meningitis results largely from activation of immune-associated pathways. We systematically investigated the production of IFN subtypes, as well as their influence on pathology, in a mouse model of S. pneumoniae meningitis. Despite the occurrence of a mixed IFN type I/II gene signature, no evidence for production or involvement of type I IFNs in disease progression was found. In contrast, type II IFN (IFN-γ) was strongly induced, and IFN-γ−/− mice were significantly protected from severe disease. Using intracellular cytokine staining and targeted cell-depletion approaches, NK cells were found to be the dominant source of IFN-γ. Furthermore, production of IFN-γ was found to be dependent upon ASC and IL-18, indicating that an ASC-dependent inflammasome pathway was responsible for mediating IFN-γ induction. The influence of IFN-γ gene deletion on a range of processes known to be involved in bacterial meningitis pathogenesis was examined. Although neutrophil numbers in the brain were similar in infected wild-type and IFN-γ−/− mice, both monocyte recruitment and CCL2 production were less in infected IFN-γ−/− mice compared with infected wild-type controls. Additionally, gene expression of NO synthase was strongly diminished in infected IFN-γ−/− mice compared with infected controls. Finally, bacterial clearance was enhanced in IFN-γ−/− mice, although the underlying mechanism remains unclear. Together, these data suggest that inflammasome-dependent IFN-γ contributes via multiple pathways to pathology during S. pneumoniae meningitis.