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

Introduction/Rationale: Individuals recovering from surgery are at risk for nosocomial pneumonia. When this occurs, the innate immune system is faced with competing inflammatory sites in the injured skin and the infected lung, raising the question of how the immune response prioritizes its response. We hypothesized that a lung infection would disrupt the normal course of wound healing.

Methods: The impact of nosocomial pneumonia on laparotomy healing was assessed using data obtained from the ACS National Surgical Quality Improvement Program database. Mouse models were also developed to assess the impact of post-operative pulmonary infection on the innate immune response. Tail skin excision was followed by pulmonary K. oxytoca infection to measure the effect on rate of wound closure. Wounding by the dorsal subcutaneous implantation of polyvinyl alcohol sponges was followed by pulmonary K. oxytoca infection to assess cellular responses at the wound site.

Results: Laparotomy data showed that patients with pneumonia had higher rates of wound dehiscence. In mice, lung infection slowed skin wound closure and impaired wound innate immune responses. Wound fluid IL-1b and downstream chemokines were rapidly suppressed following lung infection. Local administration of rIL-1b and chemokines in mice with lung infection rescued wound inflammation, but at the expense of lung bacterial clearance. IL-1 is regulated by signaling inhibitors. IL-1RA, a non-signaling ligand of the IL-1 receptor, was upregulated in the bronchoalveolar lavage fluid and plasma of lung-infected mice. Lung infection also increased the expression of the IL-1 receptor decoy, IL-1R2, on blood and wound neutrophils. Administration of IL-1RA to wounded mice phenocopied the effects of lung infection.

Conclusion: These results show that the infected lung induces systemic IL-1 signaling inhibitors as a protective mechanism to tune distal inflammation, preventing leukocyte migration to the wound and allowing the innate immune system to prioritize inflammatory sites.