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Murine GMP- and MDP-derived classical monocytes have distinct functions and fates [dataset 1]

ABSTRACT: Monocytes are ephemeral myeloid immune cells that arise from adult hematopoiesis and circulate in the blood. They comprise two main subsets, in mice defined as classical and non-classical monocytes (CM, NCM). Recent fate mapping and transcriptomic analyses revealed that CM themselves are heterogeneous. Here, we report surface markers that allow segregation of murine GMP- and MDP-derived CM, as well as their functional characterization, including fate definition following adoptive cell transfer. GMP-Mo and MDP- Mo gave equal rise to homeostatic CM progeny, such as blood NCM and gut macrophages; the cells however differentially seeded selected other tissues, including the dura mater and lung. Specifically, GMP-Mo and MDP-Mo gave rise to distinct interstitial lung macrophages, linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide evidence for the existence of two functionally distinct CM subsets in the mouse, which differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge.

ORGANISM(S): Mus musculus

PROVIDER: GSE261003 | GEO | 2024/05/04

REPOSITORIES: GEO

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Murine GMP- and MDP-derived classical monocytes have distinct functions and fates [dataset 2]

Project description:Monocytes are short-lived myeloid immune cells that arise from adult hematopoiesis and circulate for a short time in the blood. They comprise two main subsets, in mice defined as classical Ly6Chigh and non-classical Ly6Clow monocytes (CM, NCM). Recent fate mapping and transcriptomic analyses revealed that CM themselves are heterogeneous. Here, we report surface markers that allow segregation of murine GMP- and MDP-derived CM in the BM and blood. Functional characterization, including fate definition following adoptive cell transfer, established that GMP-Mo and MDP-Mo could equal rise to homeostatic CM progeny, such as NCM in blood and gut macrophages, but differentially seeded selected other tissues. Specifically, GMP-Mo and MDP-Mo gave rise to distinct interstitial lung macrophages, thus linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide comprehensive evidence for the existence of two functionally distinct CM subsets in the mouse, which differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge. Our findings are indicative of impact of monocyte ontogeny on in situ differentiation.

2024-05-04 | GSE261594 | GEO

RNA-seq of mouse myeloid progenitors reveals two independent pathways for monocyte production via GMPs and MDPs

Project description:Granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) produce monocytes during homeostasis and in response to increased demand during infection. Both progenitor populations are thought to derive from common myeloid progenitors (CMPs), and a hierarchical relationship (CMP-GMP-MDP-monocyte) is presumed to underlie monocyte differentiation. Here, however, we demonstrate that mouse MDPs arose from CMPs independently of GMPs, and that GMPs and MDPs produced monocytes via similar, but distinct, monocyte-committed progenitors. GMPs and MDPs yielded classical (Ly6Chi) monocytes with gene expression signatures that were defined by their origins and impacted their function. GMPs produced a subset of “neutrophil-like” monocytes, whereas MDPs gave rise to a subset of monocytes that yielded monocyte-derived dendritic cells. GMPs and MDPs were also independently mobilized to produce specific combinations of myeloid cell types following the injection of microbial components. Thus, the balance of GMP and MDP differentiation shapes the myeloid cell repertoire during homeostasis and following infection.

2017-11-21 | GSE88982 | GEO

scRNAseq reveals heterogeneity among mouse bone marrow Ly6Chi monocytes produced by GMPs and MDPs

2017-11-13 | GSE104478 | GEO

RNA seq analysis of human monocyte subsets in healthy and dengue subjects

Project description:In this analysis, sorted classical (CM), intermediate (IM) and non-classical (NCM) monocyte subsets from children under steady state (healthy, H) and dengue febrile illness (Dengue, D) were analyzed for their transcriptional profiles using RNA seq. The monocyte subsets were sorted from peripheral blood cells after excluding CD3, CD19, CD20, CD56, CD66b and NKp30 positive cells and then gating on HLADR positive population to identify CM, IM and NCM subsets based on surface expression of CD16 and CD14. The transcriptional profile of the three monocyte subsets was separately compared in healthy children, in dengue febrile children and in dengue versus healthy states. This study highlights hierarchy of gene expression in classical, intermediate and non-classical monocytes in healthy and dengue febrile conditions.

2022-05-16 | GSE176079 | GEO

Transcriptomic and proteomic profiling of non-classical monocytes unravels distinct pathogenic features in SLE

Project description:Current non-specific immunosuppressive treatments for Systemic Lupus Erythematosus (SLE) show modest efficacy. In SLE the monocytic/macrophage (Mo/Mφ) system plays a key role in the initiation and perpetuation of the systemic autoimmune response. However, the distinct functions of the Mo/Mφ cellular subsets remain elusive. Herein, we demonstrate a distinct proteomic and transcriptomic profile of non-classical monocytes (NCM) of active patients with SLE with enhanced inflammatory features such as deregulated DNA repair, cell cycle and enhanced IFN signaling in parallel with cell differentiation and developmental cues. Ex-vivo assays revealed an upregulation of p53 due to enhanced DNA damage along with G0 cell cycle arrest of SLE NCM indicative of an inflammatory phenotype. This aberrant profile of NCM of active patients with SLE is linked with an activated macrophage-like and enriched M1 pro-inflammatory response. We envisage that enhanced autophagy in SLE NCM may drive their differentiation towards an M1-like macrophage profile contributing to disease severity. Together, these findings provide evidence of skewed differentiation of NCM towards an M1-like macrophage phenotype as a pathogenic feature of NCM in SLE.

2023-11-21 | PXD042539 | Pride

Donor non-classical monocytes recruit recipient classical monocytes from the spleen by activating donor alveolar macrophages

Project description:Primary Graft Dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular non-classical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) are mobilized from the spleen and, upon entry into the allograft, permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flow cytometry revealed that pharmacological or genetic depletion of donor NCM abrogated CM recruitment, single-cell RNAseq identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of human and murine tissues combined with murine knockouts and chimeras indicated that while IL1β was secreted by multiple cell lineages, donor NCM were responsible for the early activation of AM and CCL2 release. IL1β production by NCM was NLRP3 inflammasome-dependent and inhibited by donor treatment using a clinically approved sulphonylurea, Glyburide. Production of CCL2 in the donor AM occurred through IL1R-dependent activation of PKC and NFκB-pathway. Accordingly, we show that IL1β-dependent paracrine interaction between donor NCM and AM leads to recruitment of host AM necessary for PGD. Since depletion of donor NCM, IL1β or IL1R antagonism, and inflammasome inhibition, abrogated recruitment of CM as well as PGD and are feasible using FDA-approved compounds, our findings have potential for immediate clinical translation.

2024-02-01 | GSE166679 | GEO

A Novel Non-Classical Monocyte-derived Macrophage Subset That Provides A Splenic Replication Niche For Intracellular Salmonella [Bulk RNA-Seq I]

Project description:Interactions between intracellular bacteria and mononuclear phagocytes give rise to diverse cellular phenotypes that may determine the outcome of infection. Recent advances in single-cell RNA-seq (scRNA-seq) have identified multiple subsets within the mononuclear population, but implications to their function during infection remain unknown. Here, we applied microscopy, flow cytometry and scRNA-seq to survey the mononuclear niche of intracellular Salmonella Typhimurium (S.Tm) during early systemic infection in mice. We describe eclipse-like growth kinetics in the spleen, with a first phase of bacterial control mediated by tissue-resident red-pulp macrophages. A second phase involved extensive bacterial replication within a newly identified macrophage population characterized by CD9 expression. Using Nr4a1e2-/- mice we established that CD9+ macrophages originated from non-classical monocytes (NCM), and NCM-depleted mice were more resistant to S.Tm infection. Our study defines a novel host-pathogen interface, with macrophage subset-specific interactions that determines early infection dynamics and the infection outcome of the entire organism.

2021-11-04 | GSE164253 | GEO

A Novel Non-Classical Monocyte-derived Macrophage Subset That Provides A Splenic Replication Niche For Intracellular Salmonella [Bulk RNA-Seq II]

2021-11-16 | GSE183728 | GEO

A Novel Non-Classical Monocyte-derived Macrophage Subset That Provides A Splenic Replication Niche For Intracellular Salmonella [scRNA-Seq]

2021-11-16 | GSE164254 | GEO

Analysis of human classical and non-classical monocytes compared to their dendritic cell counterpart.

Project description:Peripheral blood monocytes are the starting material utilized in conventional dendritic cell (DC) vaccination for the treatment of a broad range of malignancies. While the use of cytokines and growth factors to polarize monocyte-derived DC to distinct phenotypes is well-established, little is known about the contributions of distinct human monocyte subsets to monocyte-derived DC function and patient responses to vaccination. To investigate the status of monocyte subsets in cancer patients and following culture into DC, we isolated classical (C-Mo), intermediate (I-Mo), and non-classical (NC-Mo) from the peripheral blood of renal cell carcinoma (RCC) patients prior to DC vaccination (NCT00085436) and from anonymous healthy donors. Patients treated with DC vaccination who were long term survivors (>100 months survival) had a unique monocyte signature with a two-fold higher percentage of NC-Mo in pretreatment peripheral blood compared to other RCC patients. RCC patient monocytes from each subset were transcriptionally distinct from healthy donor monocytes. Further transcriptional analysis determined that each monocyte subset was characterized by a discrete gene expression profile before and after DC maturation. Phenotypic analysis showed that DC derived from NC-Mo expressed higher levels of CD80, CD83, CD86, HLA-DR, and CD40 compared to DC originating from C-Mo and secreted increased amounts of IL-12p70 following CD40L stimulation. Collectively, these findings establish that DC derived from NC-Mo are potent antigen presenting cells and provide the foundation for future vaccination strategies that enrich NC-Mo prior to DC maturation.

2019-11-15 | GSE106840 | GEO

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