Kidney Week

Abstract: TH-OR073

Macrophage Ontogeny Dictates the Spatiotemporal Accumulation and Function of Kidney-Resident Macrophages in Crescentic Glomerulonephritis (GN)

Session Information

• Glomerular Diseases: Novel Mechanisms of Injury
  October 22, 2026 | Location: Room 401, Convention Center
  Abstract Time: 04:30 PM - 04:40 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Fu, Jia, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States

Jia Fu, MD, MS

• Chang, Dongyuan, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States

Dongyuan Chang

• Sun, Zeguo, Yale School of Medicine, New Haven, Connecticut, United States

Zeguo Sun

• Zhang, Weijia, Albert Einstein College of Medicine, Bronx, New York, United States

Weijia Zhang, PhD

• D'Agati, Vivette D., New York-Presbyterian/Columbia University Irving Medical Center, New York, New York, United States

Vivette D. D'Agati, MD

• Salant, David J., Boston Medical Center, Boston, Massachusetts, United States

David J. Salant, MD

• He, John Cijiang, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States

John Cijiang He, MD, PhD, FASN

• Lee, Kyung, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States

Kyung Lee, PhD, FASN

Background

Macrophage accumulation drives crescentic GN (cGN), yet whether kidney-resident macrophages (KRMs) versus infiltrating monocytes/macrophages are primary pathogenic effectors remains unclear. We investigated the spatiotemporal dynamics and functional roles of ontogenically distinct macrophage subsets in a murine nephrotoxic serum (NTS) anti-GBM cGN model.

Methods

NTSN was established in C57BL/6J mice, and scRNA-seq of total kidney and CD45–enriched immune cells was performed. Cx3cr1–GFP and Ccr2–RFP dual–reporter chimeras were generated by transferring Ccr2–RFP bone marrow into irradiated Cx3cr1–GFP recipients, enabling fate mapping of radioresistant GFP⁺ KRMs versus donor–derived RFP⁺ CCR2–lineage infiltrating macrophages. Functional studies included clodronate liposome–mediated KRM depletion in GFP⁺/RFP⁺ chimeric mice and anti–CCL12 neutralizing antibody treatment in NTSN.

Results

scRNAseq identified two principal KRM subsets (Mrc1^hi, embryonic-derived; Ccr2^hi, monocyte-replenished) and revealed that both KRMs and infiltrating monocytes undergo robust proliferation peaking at day 5 and declining by day 10 post-NTS, indicating early in situ expansion in NTSN. Fate-mapping of GFP⁺/RFP⁺ chimeric mice demonstrated striking spatial compartmentalization: GFP⁺ KRMs concentrated in the outer medulla and corticomedullary junction, while bone marrow–derived RFP cells accumulated predominantly in the cortex and periglomerular areas. Clodronate liposomes administered prior to NTS led to further depletion of GFP⁺ pool in chimeric mice, which was associated with significant reduction in cortical RFP⁺ monocyte cortical infiltration, crescents, and albuminuria in NTSN. Ligand–receptor analysis identified Ccl12–Ccr2 as the top-ranked KRM–to–monocyte communication pair, with Ccl12 highly expressed in Mrc1^hi KRMs and colocalized with GFP⁺ cells by in situ hybridization. CCL12 neutralization reduced CCR2⁺ monocyte accumulation, histopathologic injury, and albuminuria.

Conclusion

In experimental cGN, KRMs and bone marrow–derived macrophages undergo coordinated, spatially segregated in situ expansion, with embryonic–derived, self–renewing KRMs acting as a pathogenic hub that recruits CCR2⁺ monocytes. These data identify ontogenically defined KRM subsets and the KRM–derived signaling as mechanistic drivers of cGN progression.

Funding

• NIDDK Support