Characterizing macrophage diversity in metastasis-bearing lungs reveals a lipid-associated macrophage subset

AbstractIn the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra- and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. By integration with single cell data, we spatially map tumor-associated cell types to find tertiary lymphoid-like structures, and a type I interferon response overlapping with regions of T-cell and macrophage subset colocalization. We construct a predictive model to infer presence of tertiary lymphoid-like structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define a high resolution map of cellular interactions in tumors and provide tools generalizing across tissues and diseases.

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Single cell RNA-seq in regenerative and fibrotic biomaterial environments defines new macrophage subsets

10.1101/642389 ◽

2019 ◽

Author(s):

Sven D. Sommerfeld ◽

Christopher Cherry ◽

Remi M. Schwab ◽

Liam Chung ◽

David R Maestas ◽

...

Keyword(s):

Single Cell ◽

Expression Profiles ◽

Small Population ◽

Foreign Body Response ◽

Phenotypic Characterization ◽

Sequencing Analysis ◽

Environmental Signals ◽

Macrophage Subset ◽

Macrophage Subsets

SummaryMacrophages play diverse roles in the immune response to infection, cancer, and wound healing where they respond to local environmental signals, yet identification and phenotypic characterization of functional subsets in vivo remains limited. We performed single cell RNA sequencing analysis on differentiated macrophages sorted from a biologic matrix-induced regenerative environment versus a synthetic biomaterial foreign body response (FBR), characterized by TH2/interleukin (IL)-4 and TH17/IL-17, respectively. In the regenerative environment, unbiased clustering and pseudotime analysis revealed distinct macrophage subsets responsible for antigen presentation, chemoattraction, and phagocytosis, as well as a small population with expression profiles of both dendritic cells and skeletal muscle. In the FBR environment, we identified a CD9hi+IL-36γ+ macrophage subset that expressed TH17-associated molecules characteristic of certain auto-immune responses that were virtually absent in mice lacking the IL-17 receptor. Surface marker combinations including CD9 and CD301b defined macrophage fibrotic and regenerative subsets enabling functional assessment and identification in human tissue. Application of the terminal macrophage subsets to train the SingleCellNet algorithm and comparison to human and mouse macrophages in tumor, lung, and liver suggest broad relevance of macrophage classification. These distinct macrophage subsets demonstrate previously unrecognized myeloid phenotypes involved in different tissue responses and provide new targets for potential therapeutic modulation of certain pathologic states and tissue repair.

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Folate Receptor β Regulates Integrin CD11b/CD18 Adhesion of a Macrophage Subset to Collagen

The Journal of Immunology ◽

10.4049/jimmunol.1501878 ◽

2016 ◽

Vol 197 (6) ◽

pp. 2229-2238 ◽

Cited By ~ 11

Author(s):

Christian Machacek ◽

Verena Supper ◽

Vladimir Leksa ◽

Goran Mitulovic ◽

Andreas Spittler ◽

...

Keyword(s):

Folate Receptor ◽

Macrophage Subset

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CCL18 in the Progression of Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21217955 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7955 ◽

Cited By ~ 1

Author(s):

Jan Korbecki ◽

Mateusz Olbromski ◽

Piotr Dzięgiel

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

M2 Macrophage ◽

Mesenchymal Transition ◽

Neoplastic Processes ◽

Anti Cancer ◽

Macrophage Subset ◽

Cancerous Cells ◽

Worse Prognosis

A neoplastic tumor consists of cancer cells that interact with each other and non-cancerous cells that support the development of the cancer. One such cell are tumor-associated macrophages (TAMs). These cells secrete many chemokines into the tumor microenvironment, including especially a large amount of CCL18. This chemokine is a marker of the M2 macrophage subset; this is the reason why an increase in the production of CCL18 is associated with the immunosuppressive nature of the tumor microenvironment and an important element of cancer immune evasion. Consequently, elevated levels of CCL18 in the serum and the tumor are connected with a worse prognosis for the patient. This paper shows the importance of CCL18 in neoplastic processes. It includes a description of the signal transduction from PITPNM3 in CCL18-dependent migration, invasion, and epithelial-to-mesenchymal transition (EMT) cancer cells. The importance of CCL18 in angiogenesis has also been described. The paper also describes the effect of CCL18 on the recruitment to the cancer niche and the functioning of cells such as TAMs, regulatory T cells (Treg), cancer-associated fibroblasts (CAFs) and tumor-associated dendritic cells (TADCs). The last part of the paper describes the possibility of using CCL18 as a therapeutic target during anti-cancer therapy.

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Co-culture of Spleen Stromal Cells with Bone Marrow Mononuclear Cells Leads to the Generation of A Novel Macrophage Subset

Scandinavian Journal of Immunology ◽

10.1111/sji.12133 ◽

2013 ◽

Vol 79 (1) ◽

pp. 27-36 ◽

Cited By ~ 2

Author(s):

X. Wang ◽

Y. Li ◽

H. Xiao ◽

X. Zhang ◽

J. Cao ◽

...

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Mononuclear Cells ◽

Bone Marrow Mononuclear Cells ◽

Macrophage Subset

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Macrophage Polarization during Murine Lyme Borreliosis

Infection and Immunity ◽

10.1128/iai.00369-15 ◽

2015 ◽

Vol 83 (7) ◽

pp. 2627-2635 ◽

Cited By ~ 16

Author(s):

Carrie E. Lasky ◽

Rachel M. Olson ◽

Charles R. Brown

Keyword(s):

Lyme Disease ◽

Time Course ◽

Macrophage Polarization ◽

Lyme Arthritis ◽

Macrophage Phenotype ◽

Content Type ◽

C3h Mice ◽

Inflammatory Site ◽

Macrophage Subset ◽

Inflammatory Infiltrates

Infection of C3H mice withBorrelia burgdorferi, the causative agent of Lyme disease, reliably produces an infectious arthritis and carditis that peak around 3 weeks postinfection and then spontaneously resolve. Macrophage polarization has been suggested to drive inflammation, the clearance of bacteria, and tissue repair and resolution in a variety of infectious disease models. During Lyme disease it is clear that macrophages are capable of clearingBorreliaspirochetes and exhausted neutrophils; however, the role of macrophage phenotype in disease development or resolution has not been studied. Using classical (NOS2) and alternative (CD206) macrophage subset-specific markers, we determined the phenotype of F4/80+macrophages within the joints and heart throughout the infection time course. Within the joint, CD206+macrophages dominated throughout the course of infection, and NOS2+macrophage numbers became elevated only during the peak of inflammation. We also found dual NOS2+CD206+macrophages which increased during resolution. In contrast to findings for the ankle joints, numbers of NOS2+and CD206+macrophages in the heart were similar at the peak of inflammation. 5-Lipoxygenase-deficient (5-LOX−/−) mice, which display a failure of Lyme arthritis resolution, recruited fewer F4/80+cells to the infected joints and heart, but macrophage subset populations were unchanged. These results highlight differences in the inflammatory infiltrates during Lyme arthritis and carditis and demonstrate the coexistence of multiple macrophage subsets within a single inflammatory site.

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New Insights into the Roles of Monocytes/Macrophages in Cardiovascular Calcification Associated with Chronic Kidney Disease

Toxins ◽

10.3390/toxins11090529 ◽

2019 ◽

Vol 11 (9) ◽

pp. 529 ◽

Cited By ~ 8

Author(s):

Hénaut ◽

Candellier ◽

Boudot ◽

Grissi ◽

Mentaverri ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Cellular Interactions ◽

Valvular Interstitial Cells ◽

Macrophage Subset ◽

And Oxidative Stress ◽

Pro Inflammatory Cytokines ◽

Valvular Cells

Cardiovascular disease (CVD) is an important cause of death in patients with chronic kidney disease (CKD), and cardiovascular calcification (CVC) is one of the strongest predictors of CVD in this population. Cardiovascular calcification results from complex cellular interactions involving the endothelium, vascular/valvular cells (i.e., vascular smooth muscle cells, valvular interstitial cells and resident fibroblasts), and monocyte-derived macrophages. Indeed, the production of pro-inflammatory cytokines and oxidative stress by monocyte-derived macrophages is responsible for the osteogenic transformation and mineralization of vascular/valvular cells. However, monocytes/macrophages show the ability to modify their phenotype, and consequently their functions, when facing environmental modifications. This plasticity complicates efforts to understand the pathogenesis of CVC—particularly in a CKD setting, where both uraemic toxins and CKD treatment may affect monocyte/macrophage functions and thereby influence CVC. Here, we review (i) the mechanisms by which each monocyte/macrophage subset either promotes or prevents CVC, and (ii) how both uraemic toxins and CKD therapies might affect these monocyte/macrophage functions.

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Gene Expression Profiling of Lymph Node Sub-Capsular Sinus Macrophages in Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.672123 ◽

2021 ◽

Vol 12 ◽

Author(s):

Danilo Pellin ◽

Natalie Claudio ◽

Zihan Guo ◽

Tahereh Ziglari ◽

Ferdinando Pucci

Keyword(s):

Gene Expression ◽

Lymph Node ◽

Lymph Nodes ◽

Molecular Mechanisms ◽

Tumor Formation ◽

Marker Selection ◽

Particulate Antigen ◽

Macrophage Subset ◽

Migratory Cells ◽

Anti Tumor Activity

Lymph nodes are key lymphoid organs collecting lymph fluid and migratory cells from the tissue area they survey. When cancerous cells arise within a tissue, the sentinel lymph node is the first immunological organ to mount an immune response. Sub-capsular sinus macrophages (SSMs) are specialized macrophages residing in the lymph nodes that play important roles as gatekeepers against particulate antigenic material. In the context of cancer, SSMs capture tumor-derived extracellular vesicles (tEVs), a form of particulate antigen released in high amounts by tumor cells. We and others have recently demonstrated that SSMs possess anti-tumor activity because in their absence tumors progress faster. A comprehensive profiling of SSMs represents an important first step to identify the cellular and molecular mechanisms responsible for SSM anti-tumor activity. Unfortunately, the isolation of SSMs for molecular analyses is very challenging. Here, we combined an optimized dissociation protocol, careful marker selection and stringent gating strategies to highly purify SSMs. We provide evidence of decreased T and B cell contamination, which allowed us to reveal the gene expression profile of this elusive macrophage subset. Squamous cell carcinomas induced an increase in the expression of Fc receptors, lysosomal and proteasomal enzymes in SSMs. Imaging of mouse and patient lymph nodes confirmed the presence of the top differentially expressed genes. These results suggest that SSMs respond to tumor formation by upregulating the machinery necessary for presentation of tumor particulate antigens to B cells.

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scRNA-seq Reveals A Macrophage Subset That Provides A Splenic Replication Niche For Intracellular Salmonella

10.1101/2021.01.04.425175 ◽

2021 ◽

Author(s):

Dotan Hoffman ◽

Yaara Tevet ◽

Gili Rosenberg ◽

Leia Vainman ◽

Aryeh Solomon ◽

...

Keyword(s):

Mononuclear Cells ◽

Growth Dynamics ◽

Systemic Infection ◽

Mononuclear Phagocytes ◽

Second Phase ◽

Molecular Features ◽

A Cell ◽

Macrophage Subset ◽

Cellular Phenotypes ◽

Classical Monocytes

AbstractInteractions 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 defined by unique molecular features, but the implications to their function during infection is unknown. Here, we applied high resolution kinetic analysis using 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 an 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 bacterial growth mediated by intracellular replication within a macrophage population we termed CD9 macrophages, that originate from non-classical monocytes. Nr4a1e2−/− mice, specifically depleted of non-classical monocytes but not other mononuclear cells, are more resistant to S.Tm infection. Our study underscores a cell-type specific host-pathogen interaction that determines early infection growth dynamics and has implications to the infection outcome of the entire organism.

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