ICMI 2015

F.77 IFN-γ umpires recovery from mucosal inflammation by regulating macrophage and γδ T cell homeostasis during microbial gut infection

Friday, July 17, 2015
Grand Hall and Gallery, Ground Floor & 1st Floor (Maritim Hotel)
Tamas Dolowschiak , ETH Zurich, Zurich, CH, Switzerland
Rounak Vyas , Bioinformatics Group, Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
Anna A. Mueller , Institute of Microbiology, D-BIOL, ETH Zurich, Zurich, Switzerland
Lynn Pisan , Institute of Microbiology, D-BIOL, ETH Zurich, Zurich, Switzerland
Boas Felmy , ETH Zurich, Zürich, Switzerland
Christian von Mering , Bioinformatics Group, Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
Wolf-Dietrich Hardt , Institute of Microbiology, D-BIOL, ETH Zurich, Zurich, Switzerland
Acute, self-limiting inflammatory disorders caused by pathogenic bacteria are a critical threat especially to the immunocompromised and elderly. Immune coordination of homeostasis in the gut after such microbial challenges are, however, still poorly understood. Here, we identified a resolving role of tissue resident macrophages and IL-22 released from intraepithelial T lymphocytes of the cecal mucosa in response to Salmonella Typhimurium infection at the single cell level. In detail, we established a remission model of experimental enterocolitis using ciprofloxacin, a fluoroquinolone antibiotic. While formation of persisters was observed in the intestinal wall, treatment upon infection resulted in potent elimination of Salmonella from the gut lumen, and delineated pathological changes of mucosal recovery from early acute inflammation. Defined resolution indices further specified cellular and molecular dynamics of remission during antibiotic therapy. Importantly, composition of the mucosal mononuclear phagocyte compartment, as well as regulation of T-cell derived IL-22 levels were substantial to initiate resolution of intestinal pathology and maintain gut homeostasis in an IFN-γ-dependent fashion. In conclusion, these data revealed a yet unidentified role of cecal IFN-γ and IL-22 within the recovering gut mucosa of infected animals. Understanding the dysregulation of such anti-inflammatory mechanisms upon pathogen invasion and antimicrobial therapy has a decisive importance for the future.