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

Individuals recovering from surgery are at risk of nosocomial infections such as pneumonia. In this setting, the innate immune system faces competing inflammation in the injured skin and infected lung, raising the question of how the immune response prioritizes inflammatory sites. We hypothesized that the initiation of a lung infection would disrupt wound healing. Supporting this hypothesis, data from the ACS NSQIP database showed that the rate of laparotomy dehiscence in surgical patients with pneumonia was over double the rate of those without pneumonia. We next developed mouse models of post-operative pulmonary infection to assess cellular mechanisms. Using the tail skin excision and dorsal subcutaneous PVA sponge implantation wound healing models, we found that bacterial lung infection slowed the rate of wound closure and impaired wound neutrophil, monocyte, and cytokine/chemokine responses. Lung infection quickly suppressed wound fluid IL-1b and downstream chemokine concentrations within 6 hours of inoculation. IL-1 receptor antagonist (IL-1RA), an inhibitor of IL-1 signaling, was upregulated in the bronchoalveolar lavage fluid and plasma 6 hours after lung infection. Administration of IL-1RA to the wounds of uninfected mice phenocopied the effects of lung infection. Conversely, rlL-1 b rescued wound inflammation when administered to the wounds of mice with lung infection, although this occurred at the expense of lung bacterial clearance. These results suggest that the infected lung induces IL-1RA systemically as a protective mechanism to tune inflammation at distal sites via IL-1b suppression, allowing the innate immune system to prioritize inflammatory insults.