Intestinal IL-17R Signaling Constrains IL-18-Driven Liver Inflammation by the Regulation of Microbiome-Derived Products
Patricia Castillo-dela Cruz,
Alanna G. Wanek,
Pawan Kumar,
Xiaojing An,
Waleed Elsegeiny,
William Horne,
Adam Fitch,
Ansen H.P. Burr,
Kathyayini P. Gopalakrishna,
Kong Chen,
Barbara A. Methé,
Scott W. Canna,
Timothy W. Hand,
Jay K. Kolls
Affiliations
Patricia Castillo-dela Cruz
Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Alanna G. Wanek
Departments of Medicine and Pediatrics, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
Pawan Kumar
Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Xiaojing An
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Waleed Elsegeiny
Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
William Horne
Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Adam Fitch
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Center for Medicine and the Microbiome, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Ansen H.P. Burr
Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Kathyayini P. Gopalakrishna
Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA
Kong Chen
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Barbara A. Methé
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Center for Medicine and the Microbiome, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Scott W. Canna
Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Timothy W. Hand
Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Jay K. Kolls
Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Departments of Medicine and Pediatrics, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA; Corresponding author
Summary: Interleukin (IL)-17 signaling to the intestinal epithelium regulates the intestinal microbiome. Given the reported links between intestinal dysbiosis, bacterial translocation, and liver disease, we hypothesize that intestinal IL-17R signaling plays a critical role in mitigating hepatic inflammation. To test this, we study intestinal epithelium-specific IL-17RA-deficient mice in an immune-driven hepatitis model. At the naive state, these mice exhibit microbiome dysbiosis and increased translocation of bacterial products (CpG DNA), which drives liver IL-18 production. Upon disease induction, absence of enteric IL-17RA signaling exacerbates hepatitis and hepatocyte cell death. IL-18 is necessary for disease exacerbation and is associated with increased activated hepatic lymphocytes based on Ifng and Fasl expression. Thus, intestinal IL-17R regulates translocation of TLR9 ligands and constrains susceptibility to hepatitis. These data connect enteric Th17 signaling and the microbiome in hepatitis, with broader implications on the effects of impaired intestinal immunity and subsequent release of microbial products observed in other extra-intestinal pathologies. : Castillo-dela Cruz et al. describe a unique protective role of intestinal IL-17RA in hepatitis. Disruption of intestinal IL-17RA signaling results in microbiome dysbiosis and translocation of bacterial products, specifically unmethylated CpG DNA, to the liver. This promotes IL-18 production and subsequent lymphocyte activation and cell death to exacerbate liver inflammation. Keywords: Th17, microbiome, gut-liver axis, bacterial translocation, hepatitis, IL-18, Fas ligand
