Abstract
The free fatty acid palmitate enhances MSC suppression of macrophages in a ceramide/CCL2/IL-10 dependent manner
Cytotherapy (Oxford, England), Vol.27(5 Supplement), pp.S52-S53
05/2025
DOI: 10.1016/j.jcyt.2025.03.087
Abstract
The immunosuppressive activity of human mesenchymal stromal cells (MSCs) is central to the approved and investigational use of MSC therapy in inflammatory conditions such as GvHD. External factors like cytokines and other molecules encountered in the disease microenvironment significantly influence MSC immunosuppressive function. The obese microenvironment including elevated levels of serum free fatty acids, specifically palmitate, have the potential to affect MSC therapy. For T cell suppression, it has already been shown that exposure to palmitate impairs the ability of MSCs to carry out their function. However, we do not yet understand the effects of palmitate on MSC immunosuppression of macrophages. This study focused on investigating the influence of palmitate on MSC functional capacity to suppress macrophages and to elucidate the mechanisms of action at play.
We used peripheral blood from healthy control and patients with obesity to investigate the immunosuppressive capacity for MSCs or MSCs exposed to plamitate in vitro. Following exposure to palmitate, the capacity for MSCs to alter human monocyte derived macrophage (MDM) production of TNFa and IL-10 and phenotype following LPS stimulation were investigated. Moreover, chemical anatagonists, neutralising antibodies and a biologically active, cell-permeable ceramide analog were used to uncover the mechanisms of action.
Palmitate exposure significantly increased expression of the MSC immunomodulatory factors ptgs2, il-6, ccl2 and angptl4. Palmitate exposed MSCs had significantly modulated LPS stimulated human MDMs leading to decreased TNFα and increased IL-10 production by MDMs. Using a neutralising antibody, we identified that enhanced suppression mediated by palmitate exposed MSCs involved CCL2. Using the biologically active, cell-permeable ceramide analog C2 as well as the cermide synthases inhibitor (fumonisin B1), we showed that palmitate enhanced MSC immunomodulation of MDMs via activating ceramide de novo synthesis.
Palmitate has a beneficial effect on macrophage immunomodulation by MSCs, suggesting that a high concentration of palmitate in the microenvironment likely does not negatively affect MSC therapy in conditions where MSC -macrophage interactions are central to MSC mode of action.
Details
- Title: Subtitle
- The free fatty acid palmitate enhances MSC suppression of macrophages in a ceramide/CCL2/IL-10 dependent manner
- Creators
- L. Bitterlich - National University of Ireland, MaynoothC. Tunstead - National University of Ireland, MaynoothJ.A. Ankrum - University of IowaA.E. Hogan - National University of Ireland, MaynoothK. English - National University of Ireland, Maynooth
- Resource Type
- Abstract
- Publication Details
- Cytotherapy (Oxford, England), Vol.27(5 Supplement), pp.S52-S53
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.jcyt.2025.03.087
- ISSN
- 1465-3249
- Language
- English
- Date published
- 05/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984820569602771
Metrics
1 Record Views