title: Splenic dendritic cell involvement in FXR-mediated amelioration of DSS colitis.
abstract: Inflammatory Bowel Disease (IBD) is a multifactorial disorder involving dysregulation of the immune response and bacterial translocation through the intestinal mucosal barrier. Previously, we have shown that activation of the bile acid sensor Farnesoid X Receptor (FXR), which belongs to the family of nuclear receptors, improves experimental intestinal inflammation, decreasing expression of pro-inflammatory cytokines and protecting the intestinal barrier. Here, we aimed to investigate the immunological mechanisms that ameliorate colitis when FXR is activated. We analyzed by FACS immune cell populations in mesenteric lymph nodes (MLN) and in the spleen to understand whether FXR activation alters the systemic immune response. We show that FXR activation by obeticholic acid (OCA) has systemic anti-inflammatory effects that include increased levels of plasma IL-10, inhibition of both DSS-colitis associated decrease in splenic dendritic cells (DCs) and increase in Tregs. Impact of OCA on DC relative abundance was seen in spleen but not MLN, possibly related to the increased FXR expression in splenic DCs compared to MLN DCs. Moreover, FXR activation modulates the chemotactic environment in the colonic site of inflammation, as Madcam1 expression is decreased, while Ccl25 is upregulated. Together, our data suggest that OCA treatment elicits an anti-inflammatory immune status including retention of DCs in the spleen, which is associated with decreased colonic inflammation. Pharmacological FXR activation is therefore an attractive new drug target for treatment of IBD.
authors.affiliation: Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Massafra
authors.affiliation: Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Noortje
authors.initials: N
authors.lastname: Ijssennagger
authors.affiliation: Laboratory of Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Maud
authors.initials: M
authors.lastname: Plantinga
authors.affiliation: Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Milona
authors.affiliation: Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: José M
authors.initials: JM
authors.lastname: Ramos Pittol
authors.affiliation: Laboratory of Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Boes
authors.affiliation: Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands. Electronic address: S.W.C.vanMil@umcutrecht.nl.
authors.forename: Saskia W C
authors.initials: SW
authors.lastname: van Mil
mesh_terms: D000818:Animals; D002633:Chemotaxis; D003092:Colitis / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate; D016753:Interleukin-10 / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D016264:Dextran Sulfate; D016753:Interleukin-10; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
keywords: Dendritic cells; Farnesoid X receptor; Inflammatory Bowel Disease