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Patricia Castillo, Pawan Kumar, Timothy W Hand, Jay K Kolls, Intestinal IL-17R signaling controls liver inflammation by constraining microbiome induced TLR9 signaling and IL-18 production, The Journal of Immunology, Volume 202, Issue 1_Supplement, May 2019, Page 191.16, https://doi.org/10.4049/jimmunol.202.Supp.191.16
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Abstract
Th17 cells and the intestinal microbiome have been linked to liver diseases such as autoimmune and viral hepatitis. Patients exhibit intestinal dysbiosis and increased bacterial translocation. In a mouse model of T cell mediated liver inflammation, concanavalin A (Con A) hepatitis, global Il17ra deficiency and gentamicin treatment are protective. Yet, it is unknown if IL-17 contributes to microbial dysbiosis and bacterial translocation in hepatitis, and how these factors together affect disease.
To study this, we generated intestinal epithelial-specific IL-17RA deficient mice (Il17ra fl/flx villin cre + mice). Absence of enteric IL-17R signaling induced commensal dysbiosis and increased intestinal Th17 cells and Il18. These mice were more susceptible to Con A, exhibiting worsened liver damage and lethality. Single cell RNA sequencing partnered with protein-based assays revealed elevated liver IL-18, IFNγ, and FasL in Il17ra fl/flx villin cre + mice, while cohousing and antibiotic studies implicated the microbiome in disease exacerbation. Il17ra fl/flx villin cre + mice also had increased liver CpG levels, which induced IL-18. Moreover, anti-IL18 ameliorated Con A hepatitis.
We propose that disrupted enteric IL-17 signaling promotes intestinal dysbiosis and translocation of CpG to the liver, stimulating TLR9 and IL-18 production. IL-18 then induces hepatic lymphocyte activation and cell death to worsen inflammation. Understanding the mechanism underlying exacerbated disease in Il17ra fl/flx villin cre + mice will elucidate the role of enteric Th17 and the microbiome in hepatitis, with broader implications on the effects of impaired intestinal immunity and subsequent release of microbial products seen in other diseases.
