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

K. Warmink*, M. Siebelt, P. S. Low, F. M. Riemers, B. Wang, S. G. M. Plomp, M. A. Tryfonidou, P. R. van Weeren, H. Weinans, N. M. Korthagen

*Corresponding author for this work

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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. © The Author(s) 2022.
Original languageEnglish
JournalCartilage
Volume13
Issue number1
Early online date7 Mar 2022
DOIs
Publication statusPublished - 2022
Externally publishedYes

Bibliographical note

Funding Information:
The authors would like to thank Kim van der Wurff-Jacobs, Arno Concepcion, and Jeroen van Velzen for technical assistance. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Association (grants LLP12 and LLP22).

Publisher Copyright:
© The Author(s) 2022.

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