Dataset Information

Folate Receptor Expression by Human Monocyte-Derived Macrophage Subtypes and Effects of Corticosteroids.

ABSTRACT:

Objective

Folate receptor beta (FR-β) has been used as a clinical marker and target in multiple inflammatory diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA). However, the conditions under which FR-β⁺ macrophages arise remain unclear and could be affected by corticosteroids. Therefore, we studied FR-β expression in vitro in macrophage subtypes and determined their response to triamcinolone acetonide (TA), a clinically often-used corticosteroid.

Design

Human monocyte-derived macrophages were differentiated to the known M0, M1, or M2 macrophage phenotypes. The phenotype and FR-β expression and plasticity of the macrophage subtypes were determined using flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA).

Results

FR-β expression was low in granulocyte-macrophage colony-stimulating factor (GM-CSF)-generated (M1-like) macrophages and high in macrophage colony-stimulating factor (M-CSF)-generated (M0 and M2-like) macrophages. FR-β expression remained high once the M0 or M2 macrophages were stimulated with pro-inflammatory stimuli (interferon-γ plus lipopolysaccharide) to induce M1-like macrophages. On the contrary, anti-inflammatory TA treatment skewed GM-CSF macrophage differentiation toward an M2 and FR-β⁺ phenotype.

Conclusions

As corticosteroids skewed monocytes toward an FR-β-expressing, anti-inflammatory phenotype, even in an M1 priming GM-CSF environment, FR-β has potential as a biomarker to monitor success of treatment with corticosteroids. Without corticosteroid treatment, M-CSF alone induces high FR-β expression which remains high under pro-inflammatory conditions. This explains why pro-inflammatory FR-β⁺ macrophages (exposed to M-CSF) are observed in arthritis patients and correlate with disease severity.

SUBMITTER: Warmink K

PROVIDER: S-EPMC9137314 | biostudies-literature | 2022 Jan-Mar

REPOSITORIES: biostudies-literature

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Publications

Folate Receptor Expression by Human Monocyte-Derived Macrophage Subtypes and Effects of Corticosteroids.

Warmink Kelly K Siebelt Michiel M Low Philip S PS Riemers Frank M FM Wang Bingbing B Plomp Saskia G M SGM Tryfonidou Marianna A MA van Weeren P René PR Weinans Harrie H Korthagen Nicoline M NM

Cartilage 20220101 1

<h4>Objective</h4>Folate receptor beta (FR-β) has been used as a clinical marker and target in multiple inflammatory diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA). However, the conditions under which FR-β<sup>+</sup> macrophages arise remain unclear and could be affected by corticosteroids. Therefore, we studied FR-β expression <i>in vitro</i> in macrophage subtypes and determined their response to triamcinolone acetonide (TA), a clinically often-used corticosteroid.<h4>D ...[more]

PMID: 35255727

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Project description:Background & aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear.MethodsLiver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue.ResultsWe observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocyte/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis, we demonstrate that recruitment of MdMs precedes Kupffer cell loss and liver damage. Electron microscopy of isolated macrophages revealed increased lipid accumulation in MdMs, and ex vivo lipid transfer experiments suggested that MdMs may serve a distinct role in lipid uptake during MAFLD.ConclusionsThe human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD.Impact and implicationsMetabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD.

Dataset Information

Folate Receptor Expression by Human Monocyte-Derived Macrophage Subtypes and Effects of Corticosteroids.

Objective

Design

Results

Conclusions

Publications

Folate Receptor Expression by Human Monocyte-Derived Macrophage Subtypes and Effects of Corticosteroids.

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