Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche

Bonnardel, Johnny; T’Jonck, Wouter; Gaublomme, Djoere; Browaeys, Robin; Scott, Charlotte; Martens, Liesbet; Vanneste, Bavo; Prijck, Sofie De; Nedospasov, Sergei A.; Kremer, Anna; Hamme, Evelien Van; Borghgraef, Peter; Toussaint, Wendy; Bleser, Pieter De; Mannaerts, Inge; Beschin, Alain; Grunsven, Leo A. van; Lambrecht, Bart N.; Taghon, Tom; Lippens, Saskia; Elewaut, Dirk; Saeys, Yvan; Guilliams, Martin

doi:10.1016/j.immuni.2019.08.017

Cited by 444 publications

(545 citation statements)

References 41 publications

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“…While CellPhoneDB predicts potential receptor-ligand interactions based on their expression on sender and receiver cells, it does not model the downstream transcriptional effects of these interactions. To integrate these downstream effects, we applied the NicheNet algorithm (Bonnardel et al, 2019;Browaeys et al, 2019) and focused the analysis on mono-like macrophages. First, we performed ligand activity analysis to prioritize ligands that could best predict the defined DE genes in mono-like macrophages ( Figure 6C and S6C).…”

Section: Amsmentioning

confidence: 99%

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Baßler

Fujii

Kapellos

et al. 2020

Preprint

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Despite the epidemics of chronic obstructive pulmonary disease (COPD), the cellular and molecular mechanisms of this disease are far from being understood. Here, we characterize and classify the cellular composition within the alveolar space and peripheral blood of COPD patients and control donors using a clinically applicable single-cell RNA-seq technology corroborated by advanced computational approaches for: machine learning-based cell-type classification, identification of differentially expressed genes, prediction of metabolic changes, and modeling of cellular trajectories within a patient cohort. These high-resolution approaches revealed: massive transcriptional plasticity of macrophages in the alveolar space with increased levels of invading and proliferating cells, loss of MHC expression, reduced cellular motility, altered lipid metabolism, and a metabolic shift reminiscent of mitochondrial dysfunction in COPD patients. Collectively, single-cell omics of multi-tissue samples was used to build the first cellular and molecular framework for COPD pathophysiology as a prerequisite to develop molecular biomarkers and causal therapies against this deadly disease.

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Section: Amsmentioning

confidence: 99%

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Baßler

Fujii

Kapellos

et al. 2020

Preprint

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“…While our current data clearly demonstrate that Notch2 loss-of-function promotes macrophage development from Ly6C hi monocytes and a pro-inflammatory milieu during TLR stimulation, we have previously shown that Dll1-Notch signaling promotes maturation of anti-inflammatory macrophages from Ly6C hi monocytes in ischemic muscle (Krishnasamy et al, 2017). Furthermore, Dll4-Notch signaling initiated in the liver niche was recently shown to promote Kupffer cell development after injury (Johnny Bonnardel et al, 2019;Sakai et al, 2019) or to promote pro-inflammatory macrophage development (Xu et al, 2012). This suggests that the role of Notch is ligand-, cell-and context-specific, which emphasizes the differential effects of specific ligand-receptor combinations (Benedito et al, 2009).…”

Section: Discussionmentioning

confidence: 44%

“…Notch signaling is a cell contact-dependent signaling pathway regulating cell fate decisions in the innate immune system (Radtke, Macdonald, & Tacchini-Cottier, 2013). Notch signaling regulates formation of intestinal CD11c + CX 3 CR1 + immune cells (Ishifune et al, 2014), Kupffer cells (Johnny Bonnardel et al, 2019;Sakai et al, 2019) and macrophage differentiation from Ly6C hi monocytes in ischemia (Krishnasamy et al, 2017), but also development of conventional DCs (Caton, Smith-Raska, & Reizis, 2007;Epelman et al, 2014;Lewis et al, 2011), which is mediated by Notch2.…”

Section: Introductionmentioning

confidence: 99%

Notch and TLR signaling coordinate monocyte cell fate and inflammation

Gamrekelashvili

Kapanadze

Sablotny

et al. 2020

Preprint

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Conventional Ly6C hi monocytes have developmental plasticity for a spectrum of differentiated phagocytes. Here we show, using conditional deletion strategies in a mouse model of Toll-like receptor (TLR) 7-induced inflammation, that the spectrum of developmental cell fates of Ly6C hi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6C lo patrolling monocyte development from Ly6C hi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6C lo monocyte development. At the same time, TLR7 stimulation in the absence of functional Notch2 signaling promotes resident tissue macrophage gene expression signatures in monocytes and ectopic differentiation of Ly6C hi monocytes into macrophages and dendritic cells, which appear in the blood stream and infiltrate the spleen and major blood vessels, resulting in unrestrained systemic inflammation. Thus, Notch2 is a master regulator of Ly6C hi monocyte cell fate and inflammation in response to TLR signaling.

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“…However, others were not. Bonnardel et al [129] generated RNA-seq data from purified liver sinusoidal endothelial cells (EC). We examined the profiles of the most highly-expressed EC genes in the macrophage dataset.…”

Section: Resident Macrophage Activation During Isolationmentioning

confidence: 99%

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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Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche

Cited by 444 publications

References 41 publications

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Notch and TLR signaling coordinate monocyte cell fate and inflammation

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

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