In bacterial pneumonia, lung damage resulting from epithelial cell injury is a major contributor to the severity of disease and, in some cases, can lead to long-term sequelae, especially in the setting of severe lung injury or acute respiratory distress syndrome. Leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, is a critical determinant of lung tissue protection during pneumonia, but the cellular sources of LIF and the signaling pathways leading to its production in the infected lung are not known. Here, we demonstrate that lung epithelium, specifically alveolar type II cells, is the predominant site of LIF transcript induction in pneumonic mouse lungs. Epithelial cell cultures were induced to express LIF by bacteria and by sterile bronchoalveolar lavage fluid from pneumonic mice. Reciprocal bone marrow chimera studies demonstrated that LIF deficiency in the nonhematopoietic compartment, but not LIF deficiency in hematopoietic cells, eliminated LIF induction during pneumonia. Although NF-κB RelA (p65) is essential for the expression of many cytokines during pneumonia, its targeted mutation in the lung epithelium was inconsequential for pneumonia-driven LIF induction. However, maximal expression of this epithelial-derived cytokine was dependent on NF-κB RelA in myeloid cells. Overall, our data suggest a signaling axis whereby activation of NF-κB RelA in myeloid cells promotes epithelial LIF induction during lung infections, representing a means through which these two cell types collaborate to improve tissue resilience during pneumonia.

Interleukin-11 (IL-11) is an interleukin-6 (IL-6) family cytokine shown to play a protective role in acute inflammatory settings including systemic infection. In this study we addressed the role of IL-11 in acute bacterial pneumonia using a mouse model of E. coli pneumonia. Compared with other related cytokines, IL-11 protein was maintained at high levels in the lung at baseline, with only mild alterations in whole lung and BALF levels during acute infection. The primary source of IL-11 in the lung was the epithelium, but steady state production was not dependent on the inflammatory transcription factor nuclear factor kappa B in cells of either myeloid or epithelial lineage. Blockade of IL-11 with neutralizing antibodies resulted in a mild but significant decrease in neutrophil recruitment and increase in pulmonary edema during pneumonia, without detectable alterations in bacterial clearance. Exogenous IL-11 administration, however, had no effect at baseline or during infection. Overall, we conclude that maintenance of lung IL-11 concentrations may influence acute pulmonary inflammation during infection, albeit modestly.

Identifying host factors that contribute to pneumonia incidence and severity are of utmost importance to guiding the development of more effective therapies. Lectin-like oxidized lowdensity lipoprotein receptor-1 (LOX-1) is a scavenger receptor known to promote vascular injury and inflammation, but it is unknown whether and how LOX-1 functions in the lung. Here, we provide evidence of substantial accumulation of LOX-1 in the lungs of ARDS patients and in mice with pneumonia. Unlike previously described injurious contributions of LOX-1, we found that LOX-1 is uniquely protective in the pulmonary airspaces, limiting proteinaceous edema and inflammation. We also identified alveolar macrophages and recruited neutrophils as two prominent sites of LOX-1 expression in the lungs, whereby macrophages are capable of further induction during pneumonia and neutrophils exhibit a rapid, but heterogenous elevation of LOX-1 in the infected lung. Blockade of LOX-1 led to dysregulated immune signaling in alveolar macrophages, marked by alterations in activation markers and a concomitant elevation of inflammatory gene networks. However, bone marrow chimeras also suggested a prominent role for neutrophils in LOX-1-mediated lung protection, further supported by LOX-1+ neutrophils exhibiting transcriptional changes consistent with reparative processes. Taken together, this work establishes LOX-1 as a tissue-protective factor in the lungs during pneumonia, possibly mediated by its influence on immune signaling in alveolar macrophages (AMs) and LOX-1+ airspace neutrophils.

Pneumonia is a major public health concern, causing significant morbidity and mortality annually, despite broad use of antimicrobial agents. Underlying many of the severe sequelae of acute lung infections is dysfunction of the immune response, which remains incompletely understood, yet is an attractive target of adjunct therapy in pneumonia. Here, we investigate the role of Oncostatin M (OSM), a pleiotropic cytokine of the IL-6 family, and how its signaling modulates multiple innate immune pathways during pneumonia. Previously, we have shown that OSM is necessary for neutrophil recruitment to the lungs during pneumonia by stimulating STAT3-driven CXCL5 expression. In this study, transcriptional profiling of whole lung pneumonia with OSM neutralization revealed 241 differentially expressed genes following only 6 hours of infection. Many downregulated genes are associated with STAT1, STAT3, and interferon signaling, suggesting these pathways are induced by OSM early in pneumonia. Interestingly, STAT1 and STAT3 activation was subsequently upregulated with OSM neutralization by 24 hours, suggesting that OSM interruption dysregulates these central signaling pathways. When we investigated the source of OSM in pneumonia, neutrophils, and to a lesser extent, macrophages, appear to be primary sources, suggesting a positive feedback loop of OSM production by neutrophils. From these studies we conclude that OSM produced by recruited neutrophils tunes early innate immune signaling pathways, improving pneumonia outcome.

Pneumonia and sepsis are distinct but integrally linked public health concerns. The hepatic acute-phase response (APR), which is largely dependent on transcription factors NF-B RelA and STAT3, is a hallmark of these pathologies and other injurious conditions. Inactivation of the APR can promote liver injury, a frequently observed organ dysfunction during sepsis. However, whether or how the acute-phase changes promote liver tissue resilience during infections is unclear. To determine the hepatoprotective role of the hepatic APR, we utilized mice bearing hepatocyte-specific deletions of either RelA or STAT3. Mice were challenged intratracheally (i.t.), intravenously (i.v.), or intraperitoneally (i.p.) with Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, lipopolysaccharide (LPS), or alpha-galactosylceramide (␣GalCer) to induce pneumonia, sepsis, or NKT cell activation. Liver injury was observed in RelAnull (hepRelA Δ/Δ ) mice but not STAT3-null (hepSTAT3 Δ/Δ ) mice during pneumonia. The absence of RelA resulted in hepatotoxicity across several models of pneumonia, sepsis, and NKT cell activation. Injury was associated with increased levels of activated caspase-3 and -8 and substantial alteration of the hepatic transcriptome. Hepatotoxicity in the absence of RelA could be reversed by neutralization of tumor necrosis factor alpha (TNF-␣). These results indicate the requirement of RelAdependent inducible hepatoprotection during pneumonia and sepsis. Further, the results demonstrate that RelA-dependent gene programs are critical for maintaining liver homeostasis against TNF-␣-driven immunotoxicity.