title: Continuous retinoic acid induces the differentiation of mature regulatory monocytes but fails to induce regulatory dendritic cells.
abstract: BACKGROUND
  Myeloid cells (MC) have potent immunoregulatory abilities that can be therapeutically useful to treat inflammatory disease. However, the factors which promote regulatory myeloid cell differentiation remain poorly understood. We have previously shown that estriol (E3) induces mature regulatory dendritic cells in vivo. To determine whether additional steroid hormones could induce mature regulatory myeloid cells, we investigated the effects of retinoic acid (RA) on MCs. Retinoic acid is a steroid hormone important in regulating mucosal immunity in the gut and promoting myeloid differentiation. We hypothesized that the presence of RA during differentiation would promote the formation of mature regulatory myeloid cells (MCregs).
  
  
  METHODS
  To determine RA's ability to induce regulatory myeloid cells, we differentiated bone marrow progenitor cells with granulocytic-macrophage colony-stimulating factor (GM-CSF) under the influence of RA. We found that day 7 MCs differentiated in the presence of RA had an increase in the percent positive and relative expression levels of both maturation (CD80, CD86, and MHCII) and inhibitory (PD-L1 and PD-L2) markers compared to control cells. Functionally, these day 7 RA MCs expressed increased intracellular IL-10, induced regulatory T cells in vitro compared to controls and suppressed the proliferation of responder immune cells even after inflammatory challenge with LPS.
  
  
  CONCLUSIONS
  RA induced mature regulatory myeloid cells that were suppressive and had a CD11b+ CD11c-Ly6C low/intermediate monocyte phenotype. Surprisingly, RA CD11c+ dendritic cells were not suppressive and could contribute to enhanced proliferation. These results suggest that continuous RA has unique effects on different myeloid populations during monopoeisis and dendropoiesis and promotes a population of regulatory monocytes.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: VanGundy
authors.forename: Mireia
authors.initials: M
authors.lastname: Guerau-de-Arellano
authors.forename: Julie D
authors.initials: JD
authors.lastname: Baker
authors.forename: Heather R
authors.initials: HR
authors.lastname: Strange
authors.forename: Susan
authors.initials: S
authors.lastname: Olivo-Marston
authors.forename: Dillon C
authors.initials: DC
authors.lastname: Muth
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, College of Veterinary Medicine, 370 Veterinary Medical Academic Building, 1900 Coffey Road, Columbus, OH 43210, USA. papenfuss.1@osu.edu.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Papenfuss
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; D039521:CD11c Antigen; C494192:Ly-6C antigen, mouse; D014212:Tretinoin