Peripheral Blood-Derived Mesenchymal Stem Cells Modulate Macrophage Plasticity through the IL-10/STAT3 Pathway

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells that can skew the balance of M1/M2 macrophage polarization towards the M2 phenotype via their paracrine effects, thereby promoting anatomical and functional recovery after many inflammatory diseases induced by macrophages. However, the underlying mechanism is still poorly understood. This study focused on the IL-10/STAT3 pathway and investigated whether IL-10 secreted by PBMSCs could mediate M2 polarization through the activation of this pathway. In this study, a Transwell system was used for coculturing macrophages and PBMSCs. ELISA and RT-qPCR analysis found that PBMSCs and their conditioned media (P-CM) significantly induced the expression of IL-10, while significantly inhibiting the expression of IL-1β and TNF-α; moreover, this effect could be reversed by adding Ab9969 (an IL-10 neutralizing antibody) and Stattic (a STAT3 inhibitor). Furthermore, western blotting and immunofluorescence assays demonstrated that JAK1/STAT3 signaling was significantly upregulated in macrophages cocultured with PBMSCs or P-CM, accompanied by an increase in the M2 biomarker CD206 and a decrease in the M1 biomarker CD86. This effect could also be reversed by blocking the IL-10/STAT3 pathway with Ab9969 and Stattic. In summary, PBMSCs could mediate the polarization of M2 macrophages by activating the IL-10/STAT3 pathway.

Advances in the role of STAT3 in macrophage polarization

“…Expression of pro-inflammatory mediators like cell surface receptors, chemokines, and cytokines is inhibited by the anti-inflammatory factor IL-10 ( 56 ). Additionally, research conducted by our team has demonstrated that co-culturing peripheral blood mesenchymal stem cells with macrophages can encourage the polarization of macrophages toward M2 type via the IL-10/JAK/STAT3 pathway, as well as reduce the expression and secretion of pro-inflammatory factors while increasing the expression and secretion of anti-inflammatory ones ( 57 ). In studies of enterohepatic crosstalk in nonalcoholic steatohepatitis, it has also been demonstrated that activation of this pathway promotes M2-type macrophage polarization, which ultimately attenuates the intensity of inflammation in intestinal tissues and maintains intestinal homeostasis ( 58 ).…”

The Large Molecular Weight Polysaccharide from Wild Cordyceps and Its Antitumor Activity on H22 Tumor-Bearing Mice

“…On the other hand, in this study, we also determined that IL-10 levels were significantly reduced after WCP treatment. IL-10 is an anti-inflammatory cytokine [44]. Elevated levels of IL-10 were reported to promote tumor development [45].…”

Identification of potential M2 macrophage-associated diagnostic biomarkers in coronary artery disease

“…To counteract the sustained inflammatory response and tissue damage produced by M1 macrophages, the body induces M2 macrophage polarization by activating Th2 cells to release IL-4 and IL-13 and binding IL-4R [ 33 ]. Furthermore, IL-10 can control M2 macrophage activity by stimulating the downstream STAT3 signaling pathway [ 34 ]. M2 macrophages secrete anti-inflammatory factors that antagonize the chronic inflammatory response induced by M1 macrophages; in addition, M2 macrophages have a strong phagocytic capacity to remove debris and apoptotic cells and suppress inflammation [ 35 ].…”