Palmitate enhances MSC immunomodulation of human macrophages via the ceramide/CCL2 axis in vitro

Courteney Tunstead; Laura M Bitterlich; James A Ankrum; Andrew E Hogan; Karen English

doi:10.1186/s13287-025-04536-7

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Palmitate enhances MSC immunomodulation of human macrophages via the ceramide/CCL2 axis in vitro

Journal article

Open access

Peer reviewed

Palmitate enhances MSC immunomodulation of human macrophages via the ceramide/CCL2 axis in vitro

Courteney Tunstead, Laura M Bitterlich, James A Ankrum, Andrew E Hogan and Karen English

Stem cell research & therapy, Vol.16(1), 435

08/06/2025

DOI: 10.1186/s13287-025-04536-7

PMCID: PMC12329961

PMID: 40770765

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Abstract

The immunomodulatory function of human mesenchymal stromal cells (MSCs) strongly depends on external factors; such as cytokines and other signalling molecules encountered in the disease microenvironment. An insufficiently inflammatory environment can fail to activate MSCs, and certain signals can impair their function. Obesity is on the rise worldwide, making it an additional factor to be considered prior to MSC therapy, as the microenvironment presents its own challenges. Elevated levels of serum free fatty acids, specifically palmitate, have the potential to affect MSC therapy. Palmitate-exposure has been shown to impair MSC immunomodulation of T cells in vitro. However, this is yet to be studied in the context of macrophages. MSCs from three independent donors were exposed to 0.4mM of palmitate for 6-24 h. Gene expression, protein production and functional capacity were then assessed in response to palmitate. A ceramide synthesis inhibitor (Fumonisin B1) and a CC-chemokine ligand 2 (CCL2)-neutralising antibody were further used to assess the impact of these components on palmitate-associated immunomodulation. We demonstrated that palmitate-exposed MSCs have enhanced suppression of human monocyte-derived macrophage (MDM) production of tumour necrosis factor α (TNFα), in a CCL2-dependent manner. We further elucidated parts of the pathway, such as ceramide synthesis, through which palmitate promotes this enhanced immunomodulation of macrophages. Palmitate-exposed MSCs show enhanced immunomodulation of human MDMs, through the ceramide/CCL2 axis in vitro.

Cells, Cultured

Ceramides - metabolism

Chemokine CCL2 - immunology

Chemokine CCL2 - metabolism

Humans

Immunomodulation - drug effects

Macrophages - cytology

Macrophages - drug effects

Macrophages - immunology

Macrophages - metabolism

Mesenchymal Stem Cells - cytology

Mesenchymal Stem Cells - drug effects

Mesenchymal Stem Cells - immunology

Mesenchymal Stem Cells - metabolism

Palmitates - pharmacology

Signal Transduction - drug effects

Tumor Necrosis Factor-alpha - metabolism

Details

Title: Subtitle: Palmitate enhances MSC immunomodulation of human macrophages via the ceramide/CCL2 axis in vitro
Creators: Courteney Tunstead - National University of Ireland, Maynooth
Laura M Bitterlich - National University of Ireland, Maynooth
James A Ankrum - University of Iowa
Andrew E Hogan - National University of Ireland, Maynooth
Karen English - National University of Ireland, Maynooth
Resource Type: Journal article
Publication Details: Stem cell research & therapy, Vol.16(1), 435
DOI: 10.1186/s13287-025-04536-7
PMID: 40770765
PMCID: PMC12329961
NLM abbreviation: Stem Cell Res Ther
ISSN: 1757-6512
eISSN: 1757-6512
Publisher: BMC
Grant note: 16/RI/3399 / Science Foundation Ireland John & Pat Hume Doctoral Award / National University of Ireland, Maynooth 20/FFP-A/8948 / Science Foundation Ireland
Language: English
Date published: 08/06/2025
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984945088302771

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