Mesenchymal stromal cells can block palmitate training of macrophages via cyclooxygenase-2 and interleukin-1 receptor antagonist

• Published in: Cytotherapy (Oxford, England) England), 2025-02, Vol.27 (2), p.169-180
• Main Authors: Bitterlich, Laura M., Tunstead, Courteney, Hogan, Andrew E., Ankrum, James A., English, Karen
• Format: Article
• Language: English
• Subjects: Animals; Cyclooxygenase 2 - metabolism; Humans; innate training; Interleukin 1 Receptor Antagonist Protein - metabolism; Interleukin-6 - metabolism; Lipopolysaccharides - pharmacology; macrophages; Macrophages - metabolism; Mesenchymal Stem Cells - metabolism; mesenchymal stromal cells; Mice; obesity; palmitate; Palmitates - pharmacology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1465-3249; 1477-2566; 1477-2566
• DOI: 10.1016/j.jcyt.2024.10.011

Innate training of macrophages can be beneficial for the clearance of pathogens. However, for certain chronic conditions, innate training can have detrimental effects due to an excessive production of pro-inflammatory cytokines. Obesity is a condition that is associated with a range of increased pro-inflammatory training stimuli including the free fatty acid palmitate. Mesenchymal stromal cells (MSCs) are powerful immunomodulators and known to suppress inflammatory macrophages via a range of soluble factors. We show that palmitate training of murine bone-marrow-derived macrophages and human monocyte-derived macrophages (MDMs) results in an increased production of TNFα and IL-6 upon stimulation with lipopolysaccharide and is associated with epigenetic remodeling. Palmitate training led to metabolic changes, however, MSCs did not alter the metabolic profile of human MDMs. Using a transwell system, we demonstrated that human bone marrow MSCs block palmitate training in both murine and human macrophages suggesting the involvement of secreted factors. MSC disruption of the training process occurs through more than one pathway. Suppression of palmitate-enhanced TNFα production is associated with cyclooxygenase-2 activity in MSCs, while secretion of interleukin-1 receptor antagonist by MSCs is required to suppress palmitate-enhanced IL-6 production in MDMs. [Display omitted] •Palmitate drives trained immunity in human macrophages dependent on epigenetic remodeling.•Palmitate training promotes an M2 phenotypic switch with CD206 expression.•MSCs suppress palmitate training pro-inflammatory cytokine production by macrophages.•MSCs do not alter palmitate training-induced M2 phenotypic switch.•MSCs block palmitate training of macrophages via COX-2 and IL-1Ra.