Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner

Hoeft, Konrad; Schaefer, Gideon J.L.; Kim, Hyojin; Schumacher, David; Bleckwehl, Tore; Long, Qingqing; Klinkhammer, Barbara M.; Peisker, Fabian; Koch, Lars; Nagai, James Shiniti; Halder, Maurice; Ziegler, Susanne; Liehn, Elisa A.; Kuppe, Christoph; Kranz, Jennifer; Menzel, Sylvia; Costa, Ivan G.; Wahida, Adam; Schneider, Rebekka K.; Hayat, Sikander; Kramann, Rafael

doi:10.1016/j.celrep.2023.112131

Cited by 50 publications

(35 citation statements)

References 84 publications

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“…Osteopontin has been identified as a biomarker for disease activity in auto-immune kidney diseases 43,44 , and is linked to kidney failure 45 and fibrosis 42,46 . Our results support previous reports identifying SPP1/TREM2 macrophages as cross-tissue regulators of fibrosis in various tissues by the induction of an injury associated phenotype 28,47 . Macrophages engaged in homeostatic processes have been shown to transit towards a fibrotic polarization state, likely in situations with unresolving inflammation.…”

Section: Discussionsupporting

confidence: 93%

Infiltrative classical monocyte-derived andSPP1lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

Vegting,

Jongejan,

Neele

et al. 2024

Preprint

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BackgroundKidney 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.MethodsHere, 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, 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.ResultsFour 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 (SPP1LAMs) 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-likeC1Qmacrophages, andSPP1LAMs. 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 infiltration and markers of acute inflammation, while interferon signaling and markers of chronicity were reduced compared to myeloperoxidase (MPO)-AGN.ConclusionsOur 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.Key points- Classical monocyte-derived macrophages are predominant in ANCA-associated glomerulonephritis and exhibit chemotactic and pro-inflammatory markers- Osteopontin/SPP1+lipid-associated macrophages (SPP1LAMs) show distinctive upregulation of fibrotic genesets- Understanding of the macrophage immune response supports exploration of macrophage-directed therapies for the treatment of autoimmune kidney diseases

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Section: Discussionsupporting

confidence: 93%

Infiltrative classical monocyte-derived andSPP1lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

Vegting,

Jongejan,

Neele

et al. 2024

Preprint

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“…It is essential to highlight that the in vivo relevance of the M1/M2 paradigm is uncertain 50 . Consistent with our findings, Arg1 expressing macrophages are deleterious and contribute to enhanced fibrosis in mouse bleomycin lung injury and MI 51,52 .…”

Section: Discussionsupporting

confidence: 92%

Hypoxia Sensing in Resident Cardiac Macrophages Regulates the Arg1 Macrophage Lineage During Ischemic Heart Injury

Kadyrov

Koenig

Amrute

et al. 2022

Preprint

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Cardiac macrophages orchestrate inflammatory responses following myocardial injury and represent powerful determinants of cardiac tissue remodeling and outcomes. Following myocardial infarction, large numbers of monocytes are recruited to the heart, infiltrate into the myocardium, and differentiate into diverse populations of macrophages and dendritic cells with divergent inflammatory and reparative transcriptional signatures. The molecular mechanisms that drive monocyte fate decisions in the injured heart remained to be defined. Here, we tested the hypothesis that macrophage hypoxia sensing regulates monocyte differentiation and cardiac remodeling following myocardial infarction. Using a mouse model of ischemia reperfusion injury, we uncovered that deletion of the hypoxia sensor, Hif1a, in macrophages resulted in increased infarct size and accelerated adverse remodeling without impacting coronary angiogenesis. Single cell RNA sequencing revealed that loss of macrophage hypoxia sensing led to an overrepresentation of a subpopulation of monocyte-derived macrophages marked by Arginase 1 (Arg1) mRNA and protein expression. Trajectory and pathway enrichment analysis predicted that Arg1+ macrophages were derived from Ly6Chi monocytes and represented an early stage of macrophage differentiation and expressed genes associated with metabolism and inflammation. Conditional deletion of Hif1a in cardiac resident macrophages and not monocyte-derived macrophages resulted in increased Arg1+ macrophage abundance and was sufficient to increase infarct size and accelerate adverse remodeling. Collectively, these findings identify hypoxia sensing in resident cardiac macrophages as a non-cell autonomous mediator of monocyte fate specification and outcomes in the context of myocardial infarction.

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“…This is in agreement with a previous study demonstrating that transient increases in immune cells, such as certain macrophage populations, are sufficient to induce fibrosis. 31 Future studies should investigate whether sustained immune cell infiltration influences the degree or development of CKD. We also observed that there was not a relative increase in kidney immune cells in human CKD samples compared with samples without CKD.…”

Section: Discussionmentioning

confidence: 99%

Natural Killer Lymphocytes Mediate Renal Fibrosis Due to Acute Cardiorenal Syndrome

Burfeind,

Funahashi,

Munhall

et al. 2023

Kidney360

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Background: The acute kidney injury (AKI) to chronic kidney disease (CKD) transition presents an opportunity for intervention to prevent CKD. Our lab developed a novel murine model of AKI-CKD transition, cardiac arrest and cardiopulmonary resuscitation (CA/CPR), in which all animals develop CKD at 7 weeks. The purpose of this study was to identify potential immune drivers of fibrosis after CA/CPR. Methods: Cardiac arrest was induced by potassium chloride and mice were resuscitated with chest compressions and epinephrine. The kidney immune landscape after CA/CPR was profiled using 11-color flow cytometry analysis and immunofluorescence. Immune cell-derived mediators of fibrosis were identified by analyzing data from three previously published single cell or single nuclear RNA sequencing (sc/snRNASeq) studies. NRK49F fibroblasts were treated with granzyme A (GzA) in vitro, then cell proliferation was quantified using 5-ethynyl-2′-deoxyuridine. GzA was pharmacologically inhibited both in vitro and in vivo. Results: Immune cells infiltrated the kidney after CA/CPR, consisting primarily of innate immune cells, including monocytes/macrophages, neutrophils, and natural killer (NK) cells. NK cell infiltration immediately preceded mesenchymal cell expansion, which occurred starting 7 days after CA/CPR. Immune cells colocalized with mesenchymal cells, accumulating in areas of fibrosis. Analysis of previously published sc/snRNASeq data revealed GzA as a potential mediator of immune to mesenchymal communication. GzA administration to fibroblasts in vitro induced cell growth and proliferation. Pharmacologic blockade of GzA signaling in vivo attenuated fibrosis and improved renal function after CA/CPR Conclusion: Renal inflammation occurs during cardiorenal syndrome, which correlates with mesenchymal cell expansion. GzA, produced by NK cells, presents a novel therapeutic target to prevent the transition to CKD after AKI.

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Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner

Cited by 50 publications

References 84 publications

Infiltrative classical monocyte-derived andSPP1lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

Infiltrative classical monocyte-derived andSPP1lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

Hypoxia Sensing in Resident Cardiac Macrophages Regulates the Arg1 Macrophage Lineage During Ischemic Heart Injury

Natural Killer Lymphocytes Mediate Renal Fibrosis Due to Acute Cardiorenal Syndrome

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