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Macrophages Driven to a Novel State of Activation Have Anti-Inflammatory Properties in Mice¹

Beate G. Brem-Exner^*,, Christine Sattler^*, James A. Hutchinson, Gudrun E. Koehl^*, Katharina Kronenberg^*, Stefan Farkas^*, Seiichiro Inoue^*, Christian Blank, Stuart J. Knechtle, Hans J. Schlitt^*, Fred Fändrich and Edward K. Geissler^2,*

^* Department of Surgery and Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany; Department for General and Thoracic Surgery, University Hospital, Kiel, Germany; and Department of Surgery, Division of Organ Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705

Recurrent episodes of inflammation underlie numerous pathologies, notably those of inflammatory bowel diseases. In this study, we describe a population of macrophages in a novel state of activation that mitigates colitis in mice. The cells responsible for this effect, called IFN--stimulated monocyte-derived cells (IFN-MdC), derive from mouse spleen, blood, and bone marrow monocytes and are distinguished from known macrophage populations by mode of generation, cell surface phenotype, and function. IFN-MdC only arise when macrophages are cultivated in the presence of CD40L-expressing CD4⁺ T cells, M-CSF, and IFN-. IFN-MdC express markers including F4/80, CD11b/c, CD86, and CD274; they are negative for CD4, CD8, Gr1, CD19, CD80, and CD207. Functionally, IFN-MdC are defined by their capacity to enrich cocultured T cell populations for CD4⁺CD25⁺Foxp3⁺ regulatory cells; this enrichment, constituting up to 60% or more of residual lymphocytes, is attributed to an expansion, but also to a cell contact and caspase-dependent depletion of activated T cells. In mice, IFN-MdC delivered i.v. traffic to gut-associated peripheral lymphoid tissues, including the mesenteric lymph nodes, Peyer’s patches, and colonic mucosa, and promote the clinical and histological resolution of chronic colitis. We conclude that IFN-MdC represent macrophages in a novel state of activation, possessing multiple T cell-suppressive effects with therapeutic potential for the treatment of autoimmune inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by Grant GE 1188/1-1 from the Deutsche Forschungsgemeinschaft, by the University of Regensburg Medical School Research Emphasis Program (ReFoRM C Program), and by Fresenius Biotech.

² Address correspondence and reprint requests to Dr. Edward K. Geissler, Department of Surgery, University of Regensburg, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany. E-mail address: edward.geissler{at}klinik.uni-regensburg.de

³ Abbreviations used in this paper: IFN-MdC, IFN--stimulated monocyte-derived cell; FasL, Fas ligand; DSS, dextran sulfate sodium; CD62L, CD62 ligand; Con A, concanavalin A; iNOS, inducible NO synthase; KO, knockout; LN, lymph node; L-NIL, N6-(iminoethyl)-L-lysine; 1-MT, 1-methyl-tryptophan; PD-1, programmed death receptor 1; PD-L1, programmed death receptor ligand 1; WT, wild type.

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