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

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Nies, Jasper, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  • Panzer, Ulf, University Medical Center 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

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.