title: Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile.
abstract: In recent years it has become clear that the therapeutic properties of bone marrow-derived mesenchymal stromal cells (MSC) are related not only to their ability to differentiate into different lineages but also to their capacity to suppress the immune response. We here studied the influence of MSC on macrophage function. Using mouse thioglycolate-elicited peritoneal macrophages (M) stimulated with LPS, we found that MSC markedly suppressed the production of the inflammatory cytokines TNF-alpha, IL-6, IL-12p70 and interferon-gamma while increased the production of IL-10 and IL-12p40. Similar results were observed using supernatants from MSC suggesting that factor(s) constitutively released by MSC are involved. Supporting a role for PGE(2) we observed that acetylsalicylic acid impaired the ability of MSC to inhibit the production of inflammatory cytokines and to stimulate the production of IL-10 by LPS-stimulated M. Moreover, we found that MSC constitutively produce PGE2 at levels able to inhibit the production of TNF-alpha and IL-6 by activated M. MSC also inhibited the up-regulation of CD86 and MHC class II in LPS-stimulated M impairing their ability to activate antigen-specific T CD4+ cells. On the other hand, they stimulated the uptake of apoptotic thymocytes by M. Of note, MSC turned M into cells highly susceptible to infection with the parasite Trypanosoma cruzi increasing more than 5-fold the rate of M infection. Using a model of inflammation triggered by s.c. implantation of glass cylinders, we found that MSC stimulated the recruitment of macrophages which showed a low expression of CD86 and the MHC class II molecule Ia(b) and a high ability to produce IL-10 and IL-12p40, but not IL-12 p70. In summary, our results suggest that MSC switch M into a regulatory profile characterized by a low ability to produce inflammatory cytokines, a high ability to phagocyte apoptotic cells, and a marked increase in their susceptibility to infection by intracellular pathogens.
authors.affiliation: Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Julian
authors.initials: J
authors.lastname: Maggini
authors.forename: Gerardo
authors.initials: G
authors.lastname: Mirkin
authors.forename: Ianina
authors.initials: I
authors.lastname: Bognanni
authors.forename: Josefina
authors.initials: J
authors.lastname: Holmberg
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Piazzón
authors.forename: Irene
authors.initials: I
authors.lastname: Nepomnaschy
authors.forename: Héctor
authors.initials: H
authors.lastname: Costa
authors.forename: Cristian
authors.initials: C
authors.lastname: Cañones
authors.forename: Silvina
authors.initials: S
authors.lastname: Raiden
authors.forename: Mónica
authors.initials: M
authors.lastname: Vermeulen
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Geffner
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006790:Host-Parasite Interactions; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism* / Q000469:parasitology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010587:Phagocytosis; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D013864:Thioglycolates / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10