Mesenchymal Stromal Cell-Derived Microvesicles Regulate an Internal Pro-Inflammatory Program in Activated Macrophages

• Main Authors: Juan S. Henao Agudelo, Tarcio T. Braga, Mariane T. Amano, Marcos A. Cenedeze, Regiane A. Cavinato, Amandda R. Peixoto-Santos, Marcelo N. Muscará, Simone A. Teixeira, Mario C. Cruz, Angela Castoldi, Rita Sinigaglia-Coimbra, Alvaro Pacheco-Silva, Danilo C. de Almeida, Niels Olsen Saraiva Camara
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2017-07-01
• Series: Frontiers in Immunology
• Subjects: mesenchymal stromal cells; microvesicles; macrophages; immunomodulation; acute peritonitis
• Online Access: http://journal.frontiersin.org/article/10.3389/fimmu.2017.00881/full

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 (Mϕs) remains unexplored. We investigated the immunoregulatory effect of MVs-MSCs on activated M1-Mϕs in vitro and in vivo using differentiated bone marrow Mϕs 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-Mϕs, which showed higher CD206 level and reduced CCR7 expression. This was associated with decreased levels of inflammatory molecules (IL-1β, IL-6, nitric oxide) and increased immunoregulatory markers (IL-10 and Arginase) in M1-Mϕs. In addition, we detected that MVs-MSCs promoted the downregulation of inflammatory miRNAs (miR-155 and miR-21), as well as, upregulated its predicted target gene SOCS3 in activated M1-Mϕs. In vivo MVs-MSCs treatment reduced the Mϕs infiltrate in the peritoneal cavity inducing a M2-like regulatory phenotype in peritoneal Mϕs (higher arginase activity and reduced expression of CD86, iNOS, IFN-γ, IL-1β, TNF-α, IL-1α, and IL-6 molecules). This in vivo immunomodulatory effect of MVs-MSCs on M1-Mϕs was partially associated with the upregulation of CX3CR1 in F4/80+/Ly6C+/CCR2+ Mϕs subsets. In summary, our findings indicate that MVs-MSCs can modulate an internal program in activated Mϕs establishing an alternative regulatory-like phenotype.