title: Expression of Blimp-1 in dendritic cells modulates the innate inflammatory response in dextran sodium sulfate-induced colitis.
abstract: A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103(+) dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1(cko) mice with a deletion of Blimp-1 in CD103(+) DCs and CD11c(hi) macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103(+) DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1(cko) mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow-derived DCs from Blimp-1(cko) produced increased matrix metalloproteinases in an interleukin (IL)-1β- and IL-6-dependent manner. Treatment of Blimp-1(cko) mice with anti-IL-1β and anti-IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease.
authors.affiliation: The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.|Department of Molecular Medicine, School of Medicine, Hofstra University, Hempstead, New York, United States of America.
authors.forename: Sun Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Jordan
authors.initials: J
authors.lastname: Goldstein
authors.affiliation: The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Dorso
authors.affiliation: The Human Immunology Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: The Immunology Institute, Icahn School of Medicine at Mount Sinai (deceased), New York, New York, United States of America.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Mayer
authors.affiliation: Department of Pathology and Laboratory Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, New York, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Crawford
authors.affiliation: Department of Molecular Medicine, School of Medicine, Hofstra University, Hempstead, New York, United States of America.|Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.|Department of Molecular Medicine, School of Medicine, Hofstra University, Hempstead, New York, United States of America.
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D016264:Dextran Sulfate; D006801:Humans; D008264:Macrophages / Q000276:immunology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; C513258:Prdm1 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; C087042:PRDM1 protein, human; D016264:Dextran Sulfate; D000074462:Positive Regulatory Domain I-Binding Factor 1; D020782:Matrix Metalloproteinases
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