title: Immature myeloid Gr-1+ CD11b+ cells from lipopolysaccharide-immunosuppressed mice acquire inhibitory activity in the bone marrow and migrate to lymph nodes to exert their suppressive function.
abstract: Secondary infections due to post-sepsis immunosuppression are a major cause of death in patients with sepsis. Repetitive inoculation of increasing doses of lipopolysaccharide (LPS) into mice mimics the immunosuppression associated with sepsis. Myeloid-derived suppressor cells (MDSCs, Gr-1(+) CD11b(+)) are considered a major component of the immunosuppressive network, interfering with T-cell responses in many pathological conditions. We used LPS-immunosuppressed (IS) mice to address whether MDSCs acquired their suppressive ability in the bone marrow (BM) and whether they could migrate to lymph nodes (LNs) to exert their suppressive function. Our results showed that Gr-1(+) CD11b(+) cells of IS mice already had the potential to inhibit T-cell proliferation in the BM. Moreover, soluble factors present in the BM from IS mice were responsible for inducing this inhibitory ability in control BM cells. In addition, migration of Gr-1(+) CD11b(+) to LNs in vivo was maximal when cells obtained from the BM of IS mice were inoculated into an IS context. In this regard, we found chemoattractant activity in cell-free LN extracts (LNEs) from IS mice and an increased expression of the LN-homing chemokine receptor C-C chemokine receptor type 7 (CCR7) in IS BM Gr-1(+) CD11b(+) cells. These results indicate that Gr-1(+) CD11b(+) cells found in BM from IS mice acquire their suppressive activity in the same niche where they are generated, and migrate to LNs to exert their inhibitory role. A better understanding of MDSC generation and/or regulation of factors able to induce their inhibitory function may provide new and more effective tools for the treatment of sepsis-associated immunosuppression.
authors.affiliation: Instituto de Medicina Experimental (IMEX)-CONICET/Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires, Argentina.
authors.forename: Veronica I
authors.initials: VI
authors.lastname: Landoni
authors.affiliation: Instituto de Medicina Experimental (IMEX)-CONICET/Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires, Argentina.
authors.forename: Daiana
authors.initials: D
authors.lastname: Martire-Greco
authors.affiliation: Instituto de Medicina Experimental (IMEX)-CONICET/Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires, Argentina.
authors.forename: Nahuel
authors.initials: N
authors.lastname: Rodriguez-Rodrigues
authors.affiliation: Instituto de Medicina Experimental (IMEX)-CONICET/Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires, Argentina.
authors.forename: Paula
authors.initials: P
authors.lastname: Chiarella
authors.affiliation: Instituto de Medicina Experimental (IMEX)-CONICET/Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Schierloh
authors.affiliation: Instituto de Medicina Experimental (IMEX)-CONICET/Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires, Argentina.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Isturiz
authors.affiliation: Instituto de Medicina Experimental (IMEX)-CONICET/Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires, Argentina gfernandez@hematologia.anm.edu.ar.
authors.forename: Gabriela C
authors.initials: GC
authors.lastname: Fernández
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism; D039481:CD11b Antigen / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D002633:Chemotaxis / Q000187:drug effects*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D016867:Immunocompromised Host; D008070:Lipopolysaccharides; D008198:Lymph Nodes / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; D008070:Lipopolysaccharides; C480309:Ly6G antigen, mouse; D017382:Reactive Oxygen Species; C440499:lipopolysaccharide, Escherichia coli O111 B4
keywords: MDSC; bone marrow; immunosuppression; lipopolysaccharide; mice; sepsis