Kidney Week

Abstract: TH-OR081

Kidney CCL20-CCR6 Axis Drives Th17 Recruitment in Immune Complex-Mediated Glomerulonephritis

Session Information

• Glomerular Diseases: Novel Mechanisms of Injury
  October 22, 2026 | Location: Room 401, Convention Center
  Abstract Time: 05:50 PM - 06:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Ishigaki, Sho, Cedars-Sinai, Los Angeles, California, United States

Sho Ishigaki

• Saito, Suguru, Cedars-Sinai, Los Angeles, California, United States

Suguru Saito, MD, PhD

• Kumakura, Satoshi, Cedars-Sinai, Los Angeles, California, United States

Satoshi Kumakura, PhD

• Bernstein, Ellen A., Cedars-Sinai, Los Angeles, California, United States

Ellen A. Bernstein

• Bernstein, Kenneth E., Cedars-Sinai, Los Angeles, California, United States

Kenneth E. Bernstein, MD

• Karumanchi, S. Ananth, Cedars-Sinai, Los Angeles, California, United States

S. Ananth Karumanchi, MD

• Yamashita, Michifumi, Cedars-Sinai, Los Angeles, California, United States

Michifumi Yamashita, MD, PhD, FASN

Background

T cell-driven inflammation is orchestrated by cytokine and chemokine networks that regulate T cell recruitment and activation within target tissues. Immune complex (IC) deposition is a hallmark of lupus nephritis (LN) and a major driver of kidney injury. How IC deposition remodels the intrarenal chemokine landscape to orchestrate pathogenic T cell responses remains poorly understood. We investigated whether the CCL20–CCR6 axis links IC deposition to Th17-driven inflammation in the kidney.

Methods

Human transcriptomic data from LN kidney biopsies were analyzed to assess CCL20 and CCR6 expression across renal compartments and cell types. In nephrotoxic serum nephritis (NTN), a murine model of LN (PMIDs: 40526025 and 37268107), IC deposition was pharmacologically modulated by intravenous immunoglobulin (hIVIg, 1 g/kg) administration. Genetic modulation of IC deposition was achieved using NeuACE mice overexpressing ACE in neutrophils (PMID: 35979968). Renal inflammation was assessed by flow cytometry, qPCR, and histological evaluation on periodic acid–Schiff and periodic acid-methenamine silver stainings. Immunofluorescence on paraffin and frozen sections was used to characterize CCR6⁺ T cell infiltrates. Key findings were replicated in spontaneous lupus models (NZBW F1 and NZW/BXSB mice), supporting the broader relevance of the CCL20–CCR6 axis in IC-mediated glomerulonephritis.

Results

CCL20 and CCR6 were upregulated in LN kidney biopsies, with CCL20 enriched in glomerular compartments and CCR6⁺ cells co-expressing CD3 and Th17-associated markers. In NTN mice, modulation of IC deposition, by hIVIg treatment or neutrophil-specific ACE overexpression, consistently suppressed renal Ccl20 expression, reduced accumulation of CCR6⁺ CD4⁺ T cells, and ameliorated kidney injury. Single-cell and spatial transcriptomic analyses confirmed that intrarenal CCR6⁺ CD4⁺ T cells were predominantly Th17. Notably, although CCR6 is expressed on both Th17 and regulatory T cells (Tregs), the CCL20–CCR6 axis selectively promoted Th17, but not Treg, recruitment into the inflamed kidney.

Conclusion

IC deposition drives pathogenic Th17 infiltration in LN through the CCL20–CCR6 axis, without affecting intrarenal Treg recruitment. Targeting upstream IC-mediated processes may enable selective suppression of intrarenal Th17 inflammation without compromising Treg function.

Acknowledgment

None