The Kidney Contains Ontogenetically Distinct Dendritic Cell and Macrophage Subtypes throughout Development That Differ in Their Inflammatory Properties

Salei, Natallia; Rambichler, Stephan; Salvermoser, Johanna; Papaioannou, Nikos E.; Schuchert, Ronja; Pakalniškytė, Dalia; Li, Na; Marschner, Julian A.; Lichtnekert, Julia; Stremmel, Christopher; Cernilogar, Filippo M.; Salvermoser, Melanie; Walzog, Barbara; Straub, Tobias; Schotta, Gunnar; Anders, Hans‐Joachim; Schulz, Christian; Schraml, Barbara U.

doi:10.1681/asn.2019040419

Cited by 67 publications

(108 citation statements)

References 82 publications

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“…PRJNA 544681 [70] Kidney-resident and monocyte-derived macrophage and DCs (F4/80, CD64, CD11B, CD11C, MHCII, CLEC9A lineage trace). https://doi.org/10.1371/journal.pbio.3000859.t001…”

Section: Ge131751mentioning

confidence: 99%

Network analysis of transcriptomic diversity amongst resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

2020

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The mononuclear phagocyte system (MPS) is a family of cells including progenitors, circulating blood monocytes, resident tissue macrophages, and dendritic cells (DCs) present in every tissue in the body. To test the relationships between markers and transcriptomic diversity in the MPS, we collected from National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) a total of 466 quality RNA sequencing (RNA-seq) data sets generated from mouse MPS cells isolated from bone marrow, blood, and multiple tissues. The primary data were randomly downsized to a depth of 10 million reads and requantified. The resulting data set was clustered using the network analysis tool BioLayout. A sample-to-sample matrix revealed that MPS populations could be separated based upon tissue of origin. Cells identified as classical DC subsets, cDC1s and cDC2s, and lacking Fcgr1 (encoding the protein CD64) were contained within the MPS cluster, no more distinct than other MPS cells. A gene-to-gene correlation matrix identified large generic coexpression clusters associated with MPS maturation and innate immune function. Smaller coexpression gene clusters, including the transcription factors that drive them, showed higher expression within defined isolated cells, including monocytes, macrophages, and DCs isolated from specific tissues. They include a cluster containing Lyve1 that implies a function in endothelial cell (EC) homeostasis, a cluster of transcripts enriched in intestinal macrophages, and a generic lymphoid tissue cDC cluster associated with Ccr7. However, transcripts encoding Adgre1, Itgax, Itgam, Clec9a, Cd163, Mertk, Mrc1, Retnla, and H2-a/e (encoding class II major histocompatibility complex [MHC] proteins) and many other proposed macrophage subset and DC lineage markers each had idiosyncratic expression profiles. Coexpression of immediate early genes (for example, Egr1, Fos, Dusp1) and inflammatory cytokines and chemokines (tumour necrosis factor [Tnf], Il1b, Ccl3/4) indicated that all tissue disaggregation and separation protocols activate MPS cells. Tissue-specific expression clusters indicated that all cell isolation procedures also co-purify other unrelated cell types that may interact with MPS cells in vivo. Comparative analysis of RNA-seq and single-cell RNA-seq (scRNA-seq) data from the same lung cell populations indicated that MPS

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“…PRJNA 544681 [70] Kidney-resident and monocyte-derived macrophage and DCs (F4/80, CD64, CD11B, CD11C, MHCII, CLEC9A lineage trace). https://doi.org/10.1371/journal.pbio.3000859.t001…”

Section: Ge131751mentioning

confidence: 99%

Network analysis of transcriptomic diversity amongst resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

2020

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“…We suggest that the only defensible definition of a cDC is a mononuclear phagocyte that is adapted specifically to the T cell areas of secondary lymphoid organs, responding to a specific growth factor (FLT3L) and the chemokine receptor CCR7. The kidney data [111] suggest that there is also tissue-specific adaptation of "cDC2" which may remain more "macrophage-like". In that sense cDC1 and cDC2 are no more unique than a peritoneal macrophage adapting to signals from retinoic acid via induction of Gata6.…”

Section: The Utility Of Markers and Relationships Within The Mpsmentioning

confidence: 99%

“…Although the transcription repressor gene Zbtb46, encoding a putative DC lineage marker [110] was highest in DC it was also detectable in most isolated tissue macrophages, notably in kidney and lung. Another putative DC marker gene, Clec9a [111] also clustered independently because of expression in isolated intestine, kidney, liver and lung macrophages.…”

Section: Dendritic Cell Co-expression Clustersmentioning

confidence: 99%

“…The kidney dataset included F4/80 + , CD64 + macrophages isolated from control and ischemic kidneys, further subdivided based upon expression of CD11B and CD11C [152]. Salei et al [111] recently produced RNA-seq data for isolated populations of resident macrophages, monocyte-derived cells, cDC1 and cDC2 from kidney compared to similar populations from spleen. The primary data were not available for download by our automated pipeline through the ENA at the time we pooled and froze our dataset (February 2020).…”

Section: Validation Of Co-expression Clustering With An Independent Kmentioning

confidence: 99%

“…At r ≥ 0.99 the kidney cDC2 and monocyte-derived macrophages had still not separated indicating that the expression profiles of these cell types are very similar. Salei et al [111] performed a principal components analysis based upon the 500 most variable transcripts and also identified the close relationship between cDC2 and monocyte-derived cells. Our analysis further emphasizes that the main axis of difference is between spleen macrophages and all other cells.…”

Section: Validation Of Co-expression Clustering With An Independent Kmentioning

confidence: 99%

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Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

Hume

2020

Preprint

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The mononuclear phagocyte system (MPS) is a family of cells including progenitors, circulating blood monocytes, resident tissue macrophages and dendritic cells (DC) present in every tissue in the body. To test the relationships between markers and transcriptomic diversity in the MPS, we collected from NCBI-GEO >500 quality RNA-seq datasets generated from mouse MPS cells isolated from multiple tissues. The primary data were randomly down-sized to a depth of 10 million reads and requantified. The resulting dataset was clustered using the network analysis tool Graphia. A sample-to-sample matrix revealed that MPS populations could be separated based upon tissue of origin. Cells identified as classical DC subsets, cDC1 and cDC2, and lacking Fcgr1 (CD64), were centrally-located within the MPS cluster and no more distinct than other MPS cell types. A gene-to-gene correlation matrix identified large generic co-expression clusters associated with MPS maturation and innate immune function. Smaller co-expression clusters including the transcription factors that drive them showed higher expression within defined isolated cells, including macrophages and DC from specific tissues. They include a cluster containing Lyve1 that implies a function in endothelial cell homeostasis, a cluster of transcripts enriched in intestinal macrophages and a generic cDC cluster associated with Ccr7. However, transcripts encoding many other putative MPS subset markers including Adgre1, Itgax, Itgam, Clec9a, Cd163, Mertk, Retnla and H2-A/E (class II MHC) clustered idiosyncratically and were not correlated with underlying functions. The data provide no support for the concept of markers of M2 polarization or the specific adaptation of DC to present antigen to T cells. Co-expression of immediate early genes (e.g. Egr1, Fos, Dusp1) and inflammatory cytokines and chemokines (Tnf, Il1b, Ccl3/4) indicated that all tissue disaggregation protocols activate MPS cells. Tissue-specific expression clusters indicated that all cell isolation procedures also co-purify other unrelated cell types that may interact with MPS cells in vivo. Comparative analysis of public RNA-seq and single cell RNA-seq data from the same lung cell populations showed that the extensive heterogeneity implied by the global cluster analysis may be even greater at a single cell level with few markers strongly correlated with each other. This analysis highlights the power of large datasets to identify the diversity of MPS cellular phenotypes, and the limited predictive value of surface markers to define lineages, functions or subpopulations.

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Renal Mononuclear Phagocytes in Lupus Nephritis

Davidson

2021

ACR Open Rheumatology

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Renal mononuclear phagocytes are a highly pleiotropic group of immune cells of myeloid origin that play multiple protective and pathogenic roles in tissue homeostasis, inflammation, repair, and fibrosis. Infiltration of kidneys with these cells is a hallmark of lupus nephritis and is associated with more severe disease and with increased risk of progression to end-stage renal disease. This review presents current knowledge of the diversity of these cells and their involvement in kidney inflammation and resolution and describes how they contribute to the chronic inflammation of lupus nephritis. A better understanding of the subset heterogeneity and diverse functions of mononuclear phagocytes in the lupus nephritis kidney should provide fertile ground for the development of new therapeutic approaches that promote the differentiation and survival of protective subsets while targeting pathogenic cell subsets that cause inflammation and fibrosis.

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The Kidney Contains Ontogenetically Distinct Dendritic Cell and Macrophage Subtypes throughout Development That Differ in Their Inflammatory Properties

Cited by 67 publications

References 82 publications

Network analysis of transcriptomic diversity amongst resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

Network analysis of transcriptomic diversity amongst resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

Renal Mononuclear Phagocytes in Lupus Nephritis

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