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

Abstract

Summary 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 increased epithelial turnover in multiple tissues, and the antiviral cytokines Type I interferons (IFNs) mediates 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 non-epithelial 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.

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

“…Therefore, it is likely that persistent activation of pDCs by HIV-1 infection induces IFN-I expression, which contributes to ILC3 depletion. Interestingly, a recent report suggests that chronic virus infection increases epithelial turnover in multiple tissues through IFN-I-dependent mechanisms (49). We thus postulate that sustained pDC activation and IFN-I production during persistent HIV-1 infection may possibly impair the integrity of the intestinal mucosal barrier by depleting tissueresident ILC3 cells.…”

Hepatocyte Growth Factor and MET Support Mouse Enteric Nervous System Development, the Peristaltic Response, and Intestinal Epithelial Proliferation in Response to Injury

“…Our prior studies also suggested HGF expression in the ENS (Vohra et al, 2006). Finally, we were intrigued by the protective effect of HGF in rodent colitis models (Tahara et al, 2003;Mukoyama et al, 2005;Numata et al, 2005;Oh et al, 2005;Hanawa et al, 2006;Kanbe et al, 2006), and hypothesized that this might be mediated through MET-expressing enteric neurons.…”

“…E12.5 CF-1 ENS precursor cells from dissociated bowel were immunoselected with p75NTR antibody (1:1000) and maintained in culture as previously described (Sato and Heuckeroth, 2008) except that GDNF was not included in media for cell dissociation or immunoselection. Briefly, whole bowel was treated with collagenase (0.5 mg/ml) and dispase (0.5 mg/ml), triturated, and filtered through a 40 m cell strainer before incubation with p75 NTR antibody and goat anti-rabbit-coupled paramagnetic beads (Miltenyi Biotec).…”

Type I Interferons Control Proliferation and Function of the Intestinal Epithelium

“…Ablation of Ifnar1, specifically in IECs (Ifnar1 ⌬IEC ), resulted in only a modest increase in bromodeoxyuridine (BrdU) labeling, and this increase was dependent on the changes in the commensal microbiota (16). However, neither alteration in the microbiome profile (17) nor increased IEC proliferation (17,18) was observed in mice lacking Ifnar1 in all tissues compared to wild-type mice. These data suggest either that IFN do not play an important role in regulating intestinal epithelium proliferation or that genetic differences between Ifnar1 ϩ/ϩ and Ifnar1 Ϫ/Ϫ animals are masked by additional factors.…”