Macrophages driven to a novel state of activation have anti-inflammatory properties in mice.
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-gamma-stimulated monocyte-derived cells (IFNgamma-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. IFNgamma-MdC only arise when macrophages are cultivated in the presence of CD40L-expressing CD4+ T cells, M-CSF, and IFN-gamma. IFNgamma-MdC express markers including F4/80, CD11b/c, CD86, and CD274; they are negative for CD4, CD8, Gr1, CD19, CD80, and CD207. Functionally, IFNgamma-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, IFNgamma-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 IFNgamma-MdC represent macrophages in a novel state of activation, possessing multiple T cell-suppressive effects with therapeutic potential for the treatment of autoimmune inflammation.
Brem-Exner
Beate G
BG
Department of Surgery, University of Regensburg, Germany.
Sattler
Christine
C
Hutchinson
James A
JA
Koehl
Gudrun E
GE
Kronenberg
Katharina
K
Farkas
Stefan
S
Inoue
Seiichiro
S
Blank
Christian
C
Knechtle
Stuart J
SJ
Schlitt
Hans J
HJ
Fändrich
Fred
F
Geissler
Edward K
EK
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015704:CD4 Antigens / Q000032:analysis; D019013:CD40 Antigens / Q000032:analysis; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002908:Chronic Disease; D018920:Coculture Techniques; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000637:transplantation*; D008643:Mesentery; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D017471:Receptors, Interferon; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000096743:Interferon gamma Receptor
D015704:CD4 Antigens; D019013:CD40 Antigens; D020169:Caspases; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D053645:Interleukin-2 Receptor alpha Subunit; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C498833:Foxp3 protein, mouse