Mesenchymal Stromal Cell-Derived Microvesicles Regulate An Internal Pro-Inflammatory Program In Activated M1 Macrophages.

• Grant number: 17/16215-7
• Support type: Regular Research Grants - Publications - Scientific article
• Duration: September 01, 2017 - February 28, 2018
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Niels Olsen Saraiva Câmara
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Mesenchymal stromal cells (MSCs) are multipotent cells with abilities to exert immunosuppressive response promoting tissue repair. Studies have shown that MSCs can secrete extracellular vesicles (MVs-MSCs) with similar regulatory functions to the parental cells. Furthermore, strong evidence suggesting that MVs-MSCs can modulate several immune cells (i.e. Th1, Th17 and Foxp3+ T cells). However, their precise effect on macrophages (Mxs) remains unexplored. We investigated the immunoregulatory effect of MVs-MSCs on activated M1-Mxs in vitro and in vivo using differentiated bone marrow Mxs and an acute experimental model of thioglycollate-induced peritonitis, respectively. We observed that MVs-MSCs shared surface molecules with MSCs (CD44, CD105, CD90, CD73) and expressed classical microvesicle markers (Annexin V and CD9). The in vitro treatment with MVs-MSCs exerted a regulatory-like phenotype in M1-Mxs, which showed higher CD206 level and reduced CCR7 expression. This was associated with decreased levels of inflammatory molecules (IL-1², IL-6, NO) and increased immunoregulatory markers (IL-10 and Arginase) in M1-Mxs. In addition, we detected that MVs-MSCs promoted the down-regulation of inflammatory miRNAs (miR-155 and miR-21), as well as its predicted target gene SOCS3 in activated M1-Mxs. In vivo MVs-MSCs treatment reduced the Mxs infiltrate in the peritoneal cavity inducing a M2-like regulatory phenotype in peritoneal Mxs (higher arginase activity and reduced expression of CD86, iNOS, IFN-³, IL-1², TNF-±, IL-1± and IL-6 molecules). This in vivo immunomodulatory effect of MVs-MSCs on M1-Mxs was partially associated with the up-regulation of CX3CR1 in F4/80+/Ly6C+/CCR2+ Mxs subsets. In summary, our findings indicate that MVs-MSCs can modulate an internal program in activated Mxs establishing an alternative regulatory-like phenotype. (AU)