Interleukin-27 Signaling Attenuates Renal Inflammation in Crescentic Glomerulonephritis

Background: Glomerulonephritis (GN) is a heterogeneous group of immune-mediated disorders and is a frequent cause for end-stage renal disease. CD4+ T helper cells and particularly Th17 cells have been identified as major drivers of disease, and therapeutical blockade of pro-inflammatory cytokines is currently under investigation. Here, we identified Interleukin-27 (IL-27) as a mediator of anti-inflammatory effects and potential therapeutic approach in GN. Methods: Human kidney biopsies from ANCA glomerulonephritis (ANCA-GN) patients were analyzed using spatial transcriptomics (PMID: 39300109). To investigate the influence of IL-27 signaling, we induced experimental crescentic glomerulonephritis (cGN) in IL-17A fate-mapping mice and administered recombinant IL-27. At day 10, single cell RNA-sequencing (scRNA-seq) of sorted renal leukocytes was performed. Deficiency of IL-27 signaling was investigated using a CRISPR-based conditional knockout in Th17 cells and subsequent adoptive T cell transfer into immunodeficient Rag1 mice with cGN. Renal Th17 cells were analyzed using scRNA-seq and flow cytometry at day 10 after disease induction. Results: In ANCA-GN, gene ontology (GO) enrichment analysis revealed distinct upregulation of pathways associated with T cell activation and cytokine signaling. In particular, IL-27 signaling was upregulated in inflamed compartments in the kidney. Cell-cell interaction analysis using CellChat showed signaling originating from IL-27 producing activated myeloid cells to renal T cells. Treatment with IL-27 in cGN resulted in reduced tissue damage and neutrophil infiltration, as well as ameliorated kidney function. Th17-specific knockout of Il27ra resulted in aggravated inflammation and increased IL-17A secretion by Il27ra-deficient Th17 cells. Conclusion: IL-27 signaling is present in human ANCA-GN. However, treatment with IL-27 attenuates inflammation in experimental cGN. In accordance with this, specific deletion of Il27ra aggravates disease via increased production of IL-17A by Th17 cells. This study highlights the potential of IL-27 in cGN as a new therapeutic strategy in kidney autoimmunity. Funding: Government Support – Non-U.S.