TLR9- and Src-dependent expression of Krueppel-like factor 4 controls interleukin-10 expression in pneumonia (original) (raw)
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Immunology, 2015
Streptococcus pneumoniae is a major aetiological agent of pneumonia worldwide, as well as otitis media, sinusitis, meningitis and sepsis. Recent reports have suggested that inflammation of lungs due to S. pneumoniae infection promotes bacterial dissemination and severe disease. However, the contribution of anti-inflammatory molecules to the pathogenesis of S. pneumoniae remains unknown. To elucidate whether the production of the anti-inflammatory cytokine interleukin-10 (IL-10) is beneficial or detrimental for the host during pneumococcal pneumonia, we performed S. pneumoniae infections in mice lacking IL-10 (IL-10−/− mice). The IL-10−/− mice showed increased mortality, higher expression of pro-inflammatory cytokines, and an exacerbated recruitment of neutrophils into the lungs after S. pneumoniae infection. However, IL-10−/− mice showed significantly lower bacterial loads in lungs, spleen, brain and blood, when compared with mice that produced this cytokine. Our results support the notion that production of IL-10 during S. pneumoniae infection modulates the expression of pro-inflammatory cytokines and the infiltration of neutrophils into the lungs. This feature of IL-10 is important to avoid excessive inflammation of tissues and to improve host survival, even though bacterial dissemination is less efficient in the absence of this cytokine.
Cell signaling underlying the pathophysiology of pneumonia
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2006
The symposium addressed the burgeoning interest in fundamental mechanisms underlying the onset of pneumonia. Bacteria exploit the lung's innate immune mechanism, resulting in pathophysiological cell signaling. As a consequence inflammation develops, leading to pneumonia. New mechanisms have been identified by which bacteria or bacterial products in the airway induce cross-compartmental signaling that leads to inflammatory consequences. The speakers addressed activation of the transcription factor, NF-κB occurring as a consequence of bacterial interactions with specific receptors, such as the Toll-like receptors and the TNF receptor 1 (Prince), or as a consequence of cytokine induction (Mizgerd). Also considered were mechanisms of bacterial virulence in the clinical setting (Wiener-Kronish) and the role of alveolar-capillary signaling mechanisms in the initiation of lung inflammation.
Immunology, 2015
Streptococcus pneumoniae (S. pneumoniae) is a major etiologic agent of pneumonia worldwide, as well as otitis media, sinusitis, meningitis and sepsis. Recent reports have suggested that inflammation of lungs due to S. pneumoniae infection promotes bacterial dissemination and severe disease. However, the contribution of anti-inflammatory molecules to the pathogenesis of S. pneumoniae remains unknown. To elucidate whether the production of the anti-inflammatory cytokine IL-10 is beneficial or detrimental for the host during pneumococcal pneumonia, we performed S. pneumoniae infections in mice lacking IL-10 (IL-10(-/-) mice). IL-10(-/-) mice showed increased mortality, higher expression of pro-inflammatory cytokines, and an exacerbated recruitment of neutrophils into the lungs after S. pneumoniae infection. However, IL-10(-/-) mice showed significantly less bacterial loads in lungs, spleen, brain and blood, when compared to mice that produced this cytokine. Our results support the noti...
Clinical and Experimental Immunology, 2003
SUMMARY Streptococcus pneumoniae infection may result in asymptomatic carriage, mucosal or invasive disease. We hypothesize that self-limiting or fatal disease outcome follows infection with S. pneumoniae differential activation of the host immune response. BALB/c and C57BL/6 mice were inoculated intranasally with S. pneumoniae serotype 3 strain WU2 and serotype 14 strain DW14 and mortality, bacterial load, pathological changes in the lungs and cytokines mRNA levels in the spleen were analysed. No differences between the C57BL/6 and the BALB/c inbred mice were observed except for the severity of their lung pathology and IL-4 expression. Infection of the two mouse strains with S. pneumoniae WU2 resulted in sepsis and death that occurred within 4 days post-inoculation. This death was preceded, in both mouse strains, in an increase over time of the lung bacterial load and bacteraemia. The lung pathology was characterized by diffuse pneumonia with marked congestion of the lungs. Analysi...
Role of Inflammatory Risk Factors in the Pathogenesis of Streptococcus pneumoniae
Frontiers in Immunology
Streptococcus pneumoniae (Spn) is a colonizer of the human nasopharynx (NP), causing a variety of infections in humans including otitis media, pneumonia, sepsis, and meningitis. The NP is an immune permissive site which allows for the persistence of commensal bacteria. Acute or chronic respiratory airway inflammation constitutes a significant risk factor for the manifestation of Spn infections. The inflammatory conditions caused by an upper respiratory viral infection or respiratory conditions such as allergic asthma and chronic obstructive pulmonary disorders (COPDs) are implicated in the dysregulation of airway inflammation and tissue damage, which compromise the respiratory barrier integrity. These immune events promote bacterial outgrowth leading to Spn dissemination and invasion into the bloodstream. Therefore, suppression of inflammation and restoration of respiratory barrier integrity could contain Spn infections manifesting in the backdrop of an inflammatory disease condition. The gained knowledge could be harnessed in the design of novel therapeutic interventions to circumvent Spn bacterial infections.
The Journal of Immunology, 2005
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. pne...
Infection and Immunity, 2009
Streptococcus pneumoniae is a major pathogen in humans. The pathogenicity of this organism is related to its many virulence factors, the most important of which is the thick pneumococcal capsule that minimizes phagocytosis. Another virulence-associated trait is the tendency of this bacterium to undergo autolysis in stationary phase through activation of the cell wall-bound amidase LytA, which breaks down peptidoglycan. The exact function of autolysis in pneumococcal pathogenesis is, however, unclear. Here, we show the selective and specific inefficiency of wild-type S. pneumoniae for inducing production of phagocyte-activating cytokines in human peripheral blood mononuclear cells (PBMC). Indeed, clinical pneumococcal strains induced production of 30-fold less tumor necrosis factor (TNF), 15-fold less gamma interferon (IFN-␥), and only negligible amounts of interleukin-12 (IL-12) compared with other closely related Streptococcus species, whereas the levels of induction of IL-6, IL-8, and IL-10 production were similar. If pneumococcal LytA was inactivated by mutation or by culture in a medium containing excess choline, the pneumococci induced