IL-1 signaling directs the prioritization of inflammatory sites in a model of post-operative pulmonary infection

Abstract Individuals recovering from surgery are at risk of nosocomial infections such as pneumonia. In this setting, the innate immune system faces competing inflammation in injured skin and infected lung, raising question how response prioritizes inflammatory sites. We hypothesized that initiation a lung infection would disrupt wound healing. Supporting hypothesis, data ACS NSQIP database showed rate laparotomy dehiscence surgical patients with pneumonia was over double those without next developed mouse models post-operative pulmonary to assess cellular mechanisms. Using tail excision dorsal subcutaneous PVA sponge implantation healing models, we found bacterial slowed closure impaired neutrophil, monocyte, cytokine/chemokine responses. Lung quickly suppressed fluid IL-1b downstream chemokine concentrations within 6 hours inoculation. IL-1 receptor antagonist (IL-1RA), an inhibitor signaling, upregulated bronchoalveolar lavage plasma after infection. Administration IL-1RA wounds uninfected mice phenocopied effects Conversely, rIL-1b rescued when administered infection, although occurred expense clearance. These results suggest induces systemically protective mechanism tune distal sites via suppression, allowing prioritize insults. Supported by grants Defense Advanced Research Projects Agency (DARPA), Brown University (Dean's Areas Emerging New Science Award, Carney Institute Innovation Awards), NIH (NIES T32-ES7272 Training Environmental Pathology; NIGMS COBRE Award P20GM10935, NHLBI R01 126887),