Abstract: TH-PO024
IL-17C/IL-17 receptor E Signaling in CD4+ T Cells Is Required to Promote TH17 Cell-Driven Glomerular Inflammation
Session Information
- Glomerular: Basic/Experimental Immunology and Inflammation - I
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Glomerular
- 1001 Glomerular: Basic/Experimental Immunology and Inflammation
Authors
- Nies, Jasper, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Krohn, Sonja, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Paust, Hans-Joachim, Hamburg University Hospital, Hamburg, Germany
- Riedel, Jan-Hendrik, UKE , Hamburg, Germany
- Krebs, Christian F., Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Brix, Silke R., University Hospital Hamburg-Eppendorf, Hamburg, Germany
- Kapffer, Sonja, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany
- Schmidt, Tilman, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Stahl, Rolf A., University of Hamburg, Hamburg, Germany
- Panzer, Ulf, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Group or Team Name
- Panzer Lab
Background
The IL-17 cytokine family (IL-17A-F) and their cognate receptors (IL-17RA-RE) play a unique role in organ-specific autoimmunity. So far, most studies focused on the IL-17 founding member, IL-17A, as the critical mediator of diseases. The specific function of the other IL-17 family members in immunity and inflammatory diseases is largely unclear. The aim of our study was to examine the potential role of these cytokines in human and experimental immune-mediated glomerular diseases.
Methods
Serum IL-17A/C/E/F levels of 70 patients with acute ANCA-associated crescentic GN (biopsy proven) and 20 healthy control subjects were analyzed by multiplex technology (Meso Scale Discovery). The function of IL-17 cytokines and their receptors was assessed in experimental models of glomerulonephritis.
Results
Serum IL-17C levels were significantly elevated in patients with acute ANCA-associated crescentic GN compared to healthy controls (p < 0.001). In contrast, no significant differences in serum IL-17A/F/E levels were detected between patient groups and controls. Using mouse models of crescentic GN (NTN) and pristane induced lupus nephritis, we showed that the lack of IL-17C and its unique receptor IL-17RE significantly ameliorated the course of the GN in terms of renal tissue injury and kidney function. Interventional studies using an anti-IL-17A neutralizing antibody demonstrated that this protective effect was due to a reduced Th17 response in IL-17C and IL-17RE gene-deficient mice. GN induction in bone marrow chimeric mice lacking IL-17C in either hematopoietic or tissue cells revealed that systemic and renal IL-17C is expressed by tissue resident cells and not by lymphocytes. Finally, we demonstrated that IL-17RE was predominantly expressed by CD4+ Th17 cells and that this expression is instrumental for the induction / maintenance of the Th17 responses with subsequent tissue injury in crescentic GN.
Conclusion
Our findings indicate that IL-17C promotes Th17 cell responses and autoimmune kidney disease via IL-17RE signaling on CD4+ Th17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for Th17 driven autoimmune disorders.
Funding
- Government Support - Non-U.S.