Abstract
Mesenchymal stromal cells (MSCs) are a potential therapy for many chronic inflammatory diseases due to their regenerative, immunologic and anti-inflammatory properties. The two-way dialogue between MSCs and macrophages is crucial to tissue regeneration and repair. Previous research demonstrated that murine adipose-derived MSC conditioned medium (ASCcm) reprograms macrophages to an M2-like phenotype which protects from experimental colitis and sepsis. Here, our focus was to determine the molecular mechanism of lipid droplet biogenesis in macrophages re-educated using ASCcm. Adipose-derived MSC conditioned medium promotes phosphorylation of AKT/mTOR pathway proteins in macrophages. Furthermore, increased expression of PPARγ, lipid droplet biogenesis and PGE2 synthesis were observed in M2-like phenotype macrophages (high expression of arginase 1 and elevated IL-10). Treatment with mTOR inhibitor rapamycin or PPARγ inhibitor GW9662 suppressed lipid droplets and PGE2 secretion. However, these inhibitors had no effect on arginase-1 expression. Rapamycin, but not GW9662, inhibit IL-10 secretion. In conclusion, we demonstrate major effects of ASCcm to reprogram macrophage immunometabolism through mTOR and PPARγ dependent and independent pathways.
Highlights
Recent findings place metabolic reprogramming as a key aspect of macrophage activation and function[13]
Our previous research demonstrated that adipose-derived MSC conditioned medium (ASCcm) promotes macrophage differentiation towards an M2-like phenotype, which shows high therapeutic capacity in colitis and sepsis experimental models[10]
Enhancement in IL-10 production was observed in ASCcm-reprogrammed macrophage (ASC-MΦ) unlike the control macrophage (CTRL-MΦ, non-polarized) (Fig. 1C)
Summary
Recent findings place metabolic reprogramming as a key aspect of macrophage activation and function[13]. Lipid droplets act as essential platforms for immunometabolic regulation, including lipid storage and metabolism, inflammatory lipid mediator production, and signaling pathway compartmentalization In addition to their function in fat tissues, lipid droplets increase in number and size in cells involved in inflammatory processes. E.g. sterile- or infection-driven inflammation, immune cells like macrophages, neutrophil, and eosinophils exhibit increased lipid droplet biogenesis[22,23,24]. This process has been associated with increased synthesis and the secretion of inflammatory lipid mediators, such as prostanoids and leukotrienes[25]. The mechanisms of lipid droplet biogenesis in M2-like macrophage was demonstrated for the first time
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