Tissue-specific differentiation of colonic macrophages requires TGFβ receptor-mediated signaling

Schridde, Anika; Bain, Calum C.; Mayer, Johannes U; Montgomery, Jennifer; Pollet, Émeline; Denecke, Bernd; Milling, Simon; Jenkins, Stephen J.; Dalod, Marc; Henri, Sandrine; Malissen, Bernard; Pabst, Oliver; Mowat, Alan M.

doi:10.1038/mi.2016.142

Cited by 135 publications

(204 citation statements)

References 64 publications

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“…2B). The hypothesis that 12 days were insufficient for engrafted macrophages to acquire the full gene expression profile of resident cells was furthermore corroborated by the delayed onset of MHCII (encoded by H2-ab1) expression, one of the markers for intestinal macrophage maturation 13,24 (Fig. 2C).…”

Section: Transcriptomes Of Engrafted Cells Differ From Resident Macromentioning

confidence: 80%

Defining Monocyte Differentiation into Colonic and Ileal Macrophages

Gross-Vered

Shemer

Bernshtein

et al. 2019

Preprint

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Monocytes are circulating short-lived macrophage precursors that are recruited on demand from the blood to sites of inflammation and challenge. In steady state, classical monocytes give rise to vasculature-resident cells that patrol the luminal side of the endothelium. In addition, classical monocytes feed macrophage compartments of selected organs, including barrier tissues, such as the skin and intestine, as well as the heart. Monocyte differentiation under conditions of inflammation has been studied in considerable detail. In contrast, monocyte differentiation under non-inflammatory conditions remains less well understood.Here we took advantage of a combination of cell ablation and precursor engraftment to investigate the generation of gut macrophages from monocytes. Collectively, we identify factors associated with the gradual adaptation of monocytes to tissue residency. Moreover, comparison of monocyte differentiation into the colon and ileum-resident macrophages revealed the graduated acquisition of gut segment-specific gene expression signatures.

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Section: Transcriptomes Of Engrafted Cells Differ From Resident Macromentioning

confidence: 80%

Defining Monocyte Differentiation into Colonic and Ileal Macrophages

Gross-Vered

Shemer

Bernshtein

et al. 2019

Preprint

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“…FOSB has not previously been implicated in macrophage adaptation to any niche. Unfortunately, we were not able to include data from a microarray analysis of resident colonic macrophages which identified a set of 108 genes >2-fold higher in the colon relative to other macrophage populations in the ImmGen database [100]. However, Cluster 38 confirmed the gut macrophage-specific expression of several of these transcripts including Dna1l3, Fgl2, Gpr31b, Hes1, Mmp13, Ocstamp, Pgf and Tlr12.…”

Section: Tissue-specific Macrophage Clustersmentioning

confidence: 98%

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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“…As loss of Runx3 in MNP triggers spontaneous colitis, we sought to determine whether alterations in the colonic MNP compartment in Runx3 Δ mice occur prior to the onset of colitis. Colon RM are derived from recruited circulating monocytes, which differentiate to RM in four stages (S) (SP1 to SP4) described as the "waterfall" differentiation pattern (Bain et al, 2013;Schridde et al, 2017). Under steady state conditions in WT mice, the mature anti-inflammatory SP3 and SP4 stages predominate ( Figure 3A).…”

Section: Mnp Subsetsmentioning

confidence: 99%

“…These results suggest that Runx3 function in MNP is required for the maturation of colonic monocytes into anti-inflammatory RM. The transition from SP3 to fully mature SP4 RM is characterized by increased expression of Cx3cr1 (Schridde et al, 2017). To evaluate the level of Cx3cr1 expression in Runx3 Δ versus WT RM, we generated CD11c-Runx3 Δ -Cx3cr1 GFP mice.…”

Section: Mnp Subsetsmentioning

confidence: 99%

Runx3 prevents spontaneous colitis by directing differentiation of anti-inflammatory mononuclear phagocytes

Hantisteanu

Dicken

Negreanu

et al. 2019

Preprint

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RUNX3 is one of three mammalian Runt-domain transcription factors (TFs) that regulate gene expression in several types of immune cells. Runx3-deficiency in mice is associated with a multitude of defects in the adaptive and innate immunity systems, including the development of early onset colitis. Our study reveals that conditional deletion of Runx3 specifically in mononuclear phagocytes (MNP) (MNP Runx3-/-) but not in T cells, recapitulates the early onset spontaneous colitis seen in Runx3 -/mice.We show that Runx3 is expressed in colonic MNP, including resident macrophages (RM) and the dendritic cell cDC2 subsets and its loss results in impaired differentiation/maturation of both cell types. At the transcriptome level, loss of Runx3 in RM and cDC2 was associated with upregulation of pro-inflammatory genes similar to those in the early onset IBD murine model of RM Il10r-/-. The impaired RM maturation in the absence of Runx3 was associated with a marked decrease in expression of antiinflammatory and TGFb-regulated genes. Similarly, the decreased expression of b-

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Tissue-specific differentiation of colonic macrophages requires TGFβ receptor-mediated signaling

Cited by 135 publications

References 64 publications

Defining Monocyte Differentiation into Colonic and Ileal Macrophages

Defining Monocyte Differentiation into Colonic and Ileal Macrophages

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

Runx3 prevents spontaneous colitis by directing differentiation of anti-inflammatory mononuclear phagocytes

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