Type I Interferons Link Viral Infection to Enhanced Epithelial Turnover and Repair

• Published in: Cell host & microbe 2015-01, Vol.17 (1), p.85-97
• Main Authors: Sun, Lulu, Miyoshi, Hiroyuki, Origanti, Sofia, Nice, Timothy J., Barger, Alexandra C., Manieri, Nicholas A., Fogel, Leslie A., French, Anthony R., Piwnica-Worms, David, Piwnica-Worms, Helen, Virgin, Herbert W., Lenschow, Deborah J., Stappenbeck, Thaddeus S.
• Format: Article
• Language: English
• Subjects: Animals; Epithelial Cells - drug effects; Epithelial Cells - physiology; Epithelium - immunology; Epithelium - physiology; Female; Gene Expression Profiling; GTP-Binding Proteins - deficiency; Interferon Type I - metabolism; Male; Mice, Knockout; Molecular Sequence Data; Sequence Analysis, DNA; Signal Transduction; Virus Diseases - immunology
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2014.11.004

The host immune system functions constantly to maintain chronic commensal and pathogenic organisms in check. The consequences of these immune responses on host physiology are as yet unexplored, and may have long-term implications in health and disease. We show that chronic viral infection increases epithelial turnover in multiple tissues, and the antiviral cytokines type I interferons (IFNs) mediate this response. Using a murine model with persistently elevated type I IFNs in the absence of exogenous viral infection, the Irgm1−/− mouse, we demonstrate that type I IFNs act through nonepithelial cells, including macrophages, to promote increased epithelial turnover and wound repair. Downstream of type I IFN signaling, the highly related IFN-stimulated genes Apolipoprotein L9a and b activate epithelial proliferation through ERK activation. Our findings demonstrate that the host immune response to chronic viral infection has systemic effects on epithelial turnover through a myeloid-epithelial circuit. [Display omitted] •Chronic viral infection stimulates epithelial proliferation and turnover•The antiviral cytokines type I interferons promote enhanced wound repair•Type I interferon signaling in macrophages mediates increased epithelial turnover•The interferon-stimulated genes Apol9a/b promote proliferation through epithelial ERK activation Type I interferons (IFNs) are integral antiviral cytokines. Sun et al. show that elevation of IFNs during chronic viral infection increases epithelial turnover and enhances wound repair. This effect of IFNs is driven indirectly through macrophages and mediated by the interferon-stimulated genes Apolipoprotein L9a/b through epithelial ERK activation.