View Abstract

A2705 - Il-22 Reduces Influenza Pneumonia by Promoting Thymic Integrity and T Regulatory Cell Maturation
Author Block: N. McLaughlin; Medicine, Section of Pulmonology, Tulane University Health Science Center, Metairie, LA, United States.
Rational: In the United States alone, seasonal influenza A infects between 5-20% of the population, and is associated with 20-30,000 deaths a year. Hospitalization and mortality are most often due to fulminant inflammation/acute respiratory failure (ARDS) or the development of secondary bacterial infections. Our laboratory has been focused on the IL-22/IL-22BP axis during pulmonary infection. Our published work using IL-22 knockout (IL22KO) mice has demonstrated that IL-22 is required for proper epithelial repair. Expanding upon these studies we have found IL-22 administration during infection promotes repair and unexpectedly, reduces inflammation. Similarly, we have discovered that mice lacking the soluble inhibitor, IL-22 binding protein (IL22BP), have heightened response to IL-22 and reduced inflammation. Interestingly, these mice did not display peripheral lymphopenia nor thymic atrophy, both common features of severe influenza infections. Given the importance of the thymus in the development of T-regulatory cells (nTregs) we believe that the reduced pulmonary inflammation may be due in part to maintaining an intact thymus and increased production of nTregs during influenza. Thus, we believe that IL-22 is beneficial through both direct pulmonary effects (epithelial repair and tight junction maintenance) as well as indirect regulation of inflammation through the thymus.
Hypothesis: We hypothesize that Il-22 is important for reducing pulmonary influenza induced pneumonia in part by maintaining thymic integrity and increasing nTreg production.
Methods: Wild type C57BL/6, BPKO, Foxn1creIl22Ra1flox/flox, Il22KO, Rag2-GFP, and IL22cre/+zsGreenflox/flox mice were treated with PBS or 100 p.f.u. influenza A/Pr/8 for 5 days and the thymi and lungs were harvested. Thymi and lungs were processed for frozen section immunofluorescence, paraffin embed IHC, flow cytometry, or snap frozen for RNA.
Results: Using the BPKO mice as a tool to investigate uninhibited Il-22 signaling we found that during influenza infection, there was reduced weight loss, lung leak, and reduced pulmonary pathology in the BPKO mice versus wild type mice. Looking at changes in pulmonary innate immune cells we found there was a decrease in activated t-cells. Interestingly, there was a concomitant increase in antigen specific recent thymic emigrant nTregs. Furthermore, the thymus in BPKO showed preserved thymic architecture with increased nTreg production.
Conclusions: The data presented here demonstrate a novel role for Il-22 in abrogating lung injury during acute influenza pulmonary pneumonia, where nascent nTreg production within the thymus can protect against increased pulmonary t-cell activation and overall lug inflammation.