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

Abstract

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.

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

“…Previously, we showed that pneumococcal pneumonia initiates a neutrophil response that does not require TNFR (12). In the present study, i.t.…”

“…SP3 is a virulent serotype of S. pneumoniae that readily proliferates in the lungs of WT, immunocompetent mice, resulting in ϳ100% mortality (12,34). Due to the uncontrollable growth of SP3 in the lungs, we used a less virulent and more effectively eliminated serotype of pneumococcus, SP19 (12,34), to determine requirements for RelA in bacterial killing during pneumonia.…”

“…Due to the uncontrollable growth of SP3 in the lungs, we used a less virulent and more effectively eliminated serotype of pneumococcus, SP19 (12,34), to determine requirements for RelA in bacterial killing during pneumonia. Lungs harvested from RelA-deficient mice had ϳ100-fold more viable bacteria than littermate controls expressing one or both copies of RelA (Fig.…”

“…Of the five NF-B family members, only RelA and p50 have been identified in nuclear extracts of lungs exposed to bacterial stimuli (11)(12)(13). p50-deficient mice survive to adulthood and have an exaggerated inflammatory response to Escherichia coli in the lungs, suggesting that p50 serves as a negative regulator of pulmonary innate immunity (14).…”

“…RelA nuclear translocation is also induced in the lungs during pneumococcal pneumonia (12,23), yet its functional significance is unknown. Furthermore, neither the consequence of RelA deletion nor its mechanisms of activation in alveolar epithelial cells have been determined within the context of any form of bacterial pneumonia.…”