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

Journal of the American Society of Nephrology, vol. 34, pp. 240

Abstract

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). Conclusions: 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.

Authors 13

1. Yosta Vegting

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

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

2. Aldo Jongejan

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

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

3. Annette E. Neele

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam, Netherlands;

4. Nike Claessen

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands;

5. Jesper Kers Aachen Department of Pathology, Leiden

   Leiden University Medical Center · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands;

   Leiden University Medical Center, Department of Pathology, Leiden, Netherlands;

6. Joris J. T. H. Roelofs

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands;

7. Sandrine Florquin

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands;

8. Johan willem V. Heijden

   Spaarne Ziekenhuis · Spaarne Gasthuis

   Affiliation as printed

   Spaarne Gasthuis Hospital, Department of Internal Medicine, Hoofddorp, Netherlands

9. Liffert Vogt

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

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

10. Fréderike J. Bemelman

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

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

11. Menno P.J. de Winther

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam, Netherlands;

12. Perry D. Moerland

    Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

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

13. Marc L. Hilhorst

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

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