Earliest Innate Immune Responses Require Macrophage RelA during Pneumococcal Pneumonia

Abstract

NF-κB regulates cytokine expression to initiate and control the innate immune response to lung infections. The NF-κB protein RelA is critical for pulmonary host defense during Streptococcus pneumoniae pneumonia, but the cell-specific roles of this transcription factor remain to be determined. We hypothesized that RelA in alveolar macrophages contributes to cytokine expression and host defense during pneumococcal pneumonia. To test this hypothesis, we compared mice lacking RelA exclusively in myeloid cells (RelA(Δ/Δ)) with littermate controls (RelA(F/F)). Alveolar macrophages from RelA(Δ/Δ) mice expressed no full-length RelA, demonstrating effective targeting. Alveolar macrophages from RelA(Δ/Δ) mice exhibited reduced, albeit detectable, proinflammatory cytokine responses to S. pneumoniae, compared with alveolar macrophages from RelA(F/F) mice. Concentrations of these cytokines in lung homogenates were diminished early after infection, indicating a significant contribution of macrophage RelA to the initial expression of cytokines in the lungs. However, the cytokine content in infected lungs was equivalent by 15 hours. Neutrophil recruitment during S. pneumoniae pneumonia reflected a delayed onset in RelA(Δ/Δ) mice, followed by similar rates of accumulation. Bacterial clearance was eventually effective in both genotypes, but began later in RelA(Δ/Δ) mice. Thus, during pneumococcal pneumonia, only the earliest induction of the cytokines measured depended on transcription by RelA in myeloid cells, and this transcriptional activity contributed to effective immunity.

L-Plastin Is Essential for Alveolar Macrophage Production and Control of Pulmonary Pneumococcal Infection

“…The increased pneumococcal burden in the BAL fluid of LPL Ϫ/Ϫ mice as early as 3 h after infection distinguishes our model from previous models of pneumococcal susceptibility (45)(46)(47)(48). In a recent report, neutrophilic defects in antipneumococcal killing increased the pulmonary pneumococcal burden 12 and 24 h after challenge, but differences were not observed at 6 h, a point in infection when alveolar macrophages would be expected to dominate the initial immune response (46).…”

Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells

“…in part, to improved alveolar macrophage function. Interestingly, we observed an increase in CXCL2 expression in Miwi2 -/-mice, which is derived exclusively from macrophages during early stages of pneumococcal pneumonia (34). While secretory metaplasia and hypersecretory phenotypes are pathological in many lung diseases (35), such as cystic fibrosis and asthma, it is conceivable that small increases in club cell numbers may impart improved antibacterial defenses during infection.…”

Respiratory Infection and the Impact of Pulmonary Immunity on Lung Health and Disease

“…Among hematopoietic cells, the first responders are the alveolar macrophages. When pneumococcus enters the lung, alveolar macrophages mediate the initial recognition and elaboration of cytokine signals that coordinate the earliest steps of host defense (22). The subsequent recruitment of neutrophils is needed for effective immunity against diverse microbes in the lungs.…”