Kidney Week

Abstract: TH-PO537

Classical Monocyte-Derived and Lipid-Associated TREM2+ Macrophages Orchestrate Inflammatory and Fibrotic Processes in ANCA-Associated Glomerulonephritis

Session Information

• Glomerular Diseases: From Inflammation to Fibrosis - I
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

• Vegting, Yosta, Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Section of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam, Netherlands

Yosta Vegting,

• Jongejan, Aldo, Amsterdam UMC, University of Amsterdam, Dept. of Epidemiology & Data Science (EDS), Bioinformatics Laboratory, Amsterdam, Netherlands

Aldo Jongejan,

• Neele, Annette Elise, Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam, Netherlands

Annette Elise Neele,

• Claessen, Nike, Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands

Nike Claessen,

• Kers, Jesper, Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands

Jesper Kers,

• Roelofs, Joris, Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands

Joris Roelofs,

• Florquin, Sandrine, Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands

Sandrine Florquin,

• Heijden, Johan willem Van der, Spaarne Gasthuis Hospital, Department of Internal Medicine, Hoofddorp, Netherlands

Johan willem Van der Heijden,

• Vogt, Liffert, Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Section of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam, Netherlands

Liffert Vogt,

• Bemelman, Frederike J., Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Section of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam, Netherlands

Frederike J. Bemelman,

• de Winther, Menno, Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam, Netherlands

Menno de Winther,

• Moerland, Perry, Amsterdam UMC, University of Amsterdam, Dept. of Epidemiology & Data Science (EDS), Bioinformatics Laboratory, Amsterdam, Netherlands

Perry Moerland,

• Hilhorst, Marc, Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Section of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam, Netherlands

Marc Hilhorst,

Group or Team Name

• Hilhorst Group.

Background

ANCA-associated glomerulonephritis (AGN) associates with a high risk of end-stage kidney disease. Kidney macrophage infiltration is one of the main histological hallmarks of vasculitic lesions and is strongly linked to disease activity. The role of kidney macrophages in local inflammation remains unclear. Here we investigate kidney macrophage diversity and function.

Methods

Single cell transcriptome analysis of CD45⁺ immune cells from freshly retrieved kidney biopsies of 5 AGN patients, 1 disease-control with class 2 lupus nephritis (LN), and 1 nephrectomy control (NC) was performed using 10X Genomics technology. Myeloid cells were selected and subsequently reclustered to identify disease-specific macrophage subtypes and functionality was assessed by a gene set enrichment analysis (GSEA). Validation studies were performed using flow cytometry and immunohistochemistry.

Results

Focused analysis identified 2 monocyte-derived macrophage (MDMs) clusters and 2 new TREM2⁺ lipid-associated macrophage (LAMs) subtypes, C1Q⁺ and SPP1/Osteopontin⁺ LAMs (panel A). GSEA revealed increased interferon responses in MDMs compared to LAMs (panel B), and increased TNFa signaling via NFkB in classical MDMs compared to non-classical MDMs. SPP1⁺ LAMs showed upregulation of gene sets related to fibrosis and cell cycle. Evaluating kidney macrophage subsets between diseases revealed increased % classical MDMs and LAMs in AGN (respectively, 52% and 38%) compared to NC tissue (18% and 24%) (panel C). Flow cytometric analysis identified a similar increase in peripheral blood classical monocytes during active disease (P<0.0001).

Conclusion

Classical MDMs and LAMs are the main kidney macrophage subsets present in AGN. Classical MDMs drive inflammation, whereas SPP1⁺ TREM2⁺ LAMs orchestrate fibrosis. Targeting these specific macrophage subsets may potentially reduce acute kidney injury and long-term fibrosis.