Abstract: FR-PO379

A Role for IL-27 in Limiting Renal Fibrosis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Muallem, Gaia, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Aronson, Lillian R, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Hunter, Christopher A., University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Immune processes that contribute to chronic kidney disease (CKD) represent important targets for prevention of disease in the kidney. Clinical and preclinical studies have established an association between Th17 cells and alternatively activated (M2) macrophages and renal fibrosis; however, a knowledge gap exists regarding how these cells promote fibrosis and how they may be regulated. In other systems, endogenous regulators have been used to successfully skew the immune response towards protection and away from pathology. The endogenous regulatory cytokine IL-27 has been shown to limit M2 macrophages and Th17 cells in other models of inflammation, leading to the hypothesis that it would be protective against renal fibrosis.

Methods

A) Renal fibrosis was induced in wild type (WT) C57Bl/6 mice and IL-27Rα-/- mice by unilateral ureteral obstruction (UUO). Kidneys were evaluated at day 14 post obstruction for immune cell infiltration and cytokine production by flow cytometry as well as fibrosis by trichrome staining and qPCR. B) Renal biopsy samples were collected from the following patient groups: control, CKD, diabetic kidney disease (DKD), diabetes alone (DM), and hypertension alone (HTN). Tubules were microdissected and RNA sequencing was performed on the tubular epithelium.

Results

In mice, IL-27 deficiency was associated with increased renal fibrosis, indicated by trichrome staining and higher expression of the fibrotic marker MMP9. There were increased M2 macrophages and Th17 cells in the fibrotic kidneys of IL-27Rα-/- mice with one subset of the Th17 cells also producing TNFα. IL-17 blockade in the IL-27α-/- mice attenuated fibrosis after UUO. RNA sequencing of human tubular epithelium indicated increased expression of the IL-17R in patients with kidney disease compared to controls and also a positive association of IL-17R expression with fibrosis scoring.

Conclusion

These data identify a role for IL-27 in modulating clinically relevant immune pathways in the kidney. IL-27 deficiency led to reduced renal fibrosis in mice after UUO injury and to the emergence of inflammatory Th17 responses and enhanced M2 macrophage polarization. Higher IL-17R expression was associated with increased kidney fibrosis in human samples, and blocking IL-17 abrogated renal fibrosis in IL-27α-/- mice. Further work will focus on treating WT mice with exogenous IL-27 in an attempt to ameliorate disease in the kidney.

Funding

  • Other NIH Support