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Infiltrative classical monocyte-derived and SPP1 lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

医学 巨噬细胞 炎症 川地163 免疫学 纤维化 四氯化碳 肾脏疾病 骨桥蛋白 单核细胞 肾小球肾炎 病理 趋化因子 生物 内科学 生物化学 体外
作者
Yosta Vegting,Aldo Jongejan,Annette E. Neele,Nike Claessen,Gal Sela,Koen H.M. Prange,Jesper Kers,Joris J. T. H. Roelofs,Joost W van der Heijden,Onno J. de Boer,Ester B. M. Remmerswaal,Liffert Vogt,Fréderike J. Bemelman,Menno P.J. de Winther,Perry D. Moerland,Marc Hilhorst
出处
期刊:Nephrology Dialysis Transplantation [Oxford University Press]
标识
DOI:10.1093/ndt/gfae292
摘要

Abstract Background and hypothesis Kidney macrophage infiltration is a histological hallmark of vasculitic lesions and is strongly linked to disease activity in anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AGN). The precise mechanisms by which kidney macrophages influence local inflammation and long-term damage remain largely unknown. Methods Here, we investigate kidney macrophage diversity using single-cell transcriptome analysis of 25 485 freshly retrieved unfrozen, high-quality kidney CD45+ immune cells from five AGN patients during active disease, a lupus nephritis and nephrectomy control. Detailed subclustering of myeloid cells was performed to identify disease-specific macrophage subtypes. Next, transcriptome differences between macrophage subsets and disease serotypes were assessed. Findings were validated by immunostainings of an extended cohort of kidney biopsies and flow cytometric analysis of peripheral blood monocytes. Results Four main macrophage subsets were identified, including a classical monocyte-derived macrophage (MDM) subset expressing a chemotactic (CXCL2, CXCL3, CXCL8, CCL3) and pro-inflammatory (IL1β, TNF) set of markers and a osteopontin/SPP1+ lipid-associated macrophage (SPP1 LAMs) subtype exhibiting distinctive upregulation of fibrotic genesets. AGN samples revealed a markedly increased proportion of CD163+ macrophages, predominantly composed of classical MDMs, accompanied by resident-like C1Q macrophages, and SPP1 LAMs An analogous trend was observed in the expansion of peripheral blood classical monocytes during active disease. The proteinase 3 (PR3)-AGN subtype exhibited heightened classical MDM and SPP1 LAM infiltration and markers of acute inflammation, while interferon signaling and markers of chronicity were reduced compared to myeloperoxidase (MPO)-AGN. Conclusions Our findings highlight the expression of inflammatory and fibrotic genes by kidney macrophage subsets in AGN. Classical monocyte dysregulation might contribute to inflammation in the pathogenesis of AGN. Targeting these specific monocyte/macrophage subsets may potentially control the inflammatory cascade and attenuate resulting fibrosis in AGN and kidney disease in general.

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