Continuous retinoic acid induces the differentiation of mature regulatory monocytes but fails to induce regulatory dendritic cells

Abstract

BackgroundMyeloid 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).MethodsTo 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.ConclusionRA 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.

The CD14+HLA-DRlo/neg Monocyte: An Immunosuppressive Phenotype That Restrains Responses to Cancer Immunotherapy

“…Myeloid cells that suppress the immune system have been described by a variety of names including myeloid derived suppressor cells (MDSCs), M2 monocytes/macrophages, tumor associated macrophages/myeloid cells, and regulatory myeloid cells (1–3). They are a heterogeneous population comprised of precursors of granulocytes, macrophages, and dendritic cells (DC).…”

“…As evidence for the role of immunosuppressive monocytes in inhibiting anti-tumor responses continues to build, it becomes readily apparent that therapeutically targeting these cells should improve responses to immunotherapy. Agents designed to interfere with MDSCs have generally been classified into four categories: (1) inhibition of the conversion, appearance and/or expansion of MDSCs, (2) inhibition of MDSC immunosuppressive functions, (3) interference of MDSC trafficking to tumors, and (4) direct removal and cytotoxic approaches (89–91). Several agents that interfere with these mechanisms have shown promise in pre-clinical animal studies and have been reviewed elsewhere (89–93).…”

Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration

“…The murine tumor models utilized in these experiments to obtain MDSC were pancreatic cancer (Panc02) and melanoma (B16-F10) 38 , 47 , 48 . After 48 hours, the cells were pulsed with 3 H thymidine, harvested 18 hours later, and measured for uptake of 3 H thymidine as previously described 49 . These experiments were repeated in the presence of a NO donor SNAP (S-Nitroso-N-Acetyl-D,L-Penicillamine; Fisher Scientific, Hampton, NH) or DETA-NONOate (Diethylenetriamine NONOate; Cayman Chemical, Ann Arbor, MI).…”

Detección y expresión de los receptores X retinoicos (RXR) en la mucosa yeyunal de crías de alpacas (Vicugna pacos)

“…Las células T y B de alojamiento (homing) en el intestino son las células que juegan un papel esencial en la protección del tracto digestivo frente a patógenos (McGhee y Fujihashi, 2012). El ácido retinoico también participa en la producción de fagocitos maduros en la medula ósea, produciendo monocitos CD11b+ CD11c-Ly6C bajo/intermedio con fenotipo supresor y células dendríticas CD11c + no supresoras que podrían contribuir a una mayor proliferación celular (VanGundy et al, 2014). Además el ácido retinoico producido localmente en la mucosa intestinal induce a la proliferación de células T reguladoras (activadas por el activador transcripcional FoxP3) que son importantes para el mantenimiento de la tolerancia inmune en el intestino; cumpliendo roles antagónicos que permiten la homeostasis de la función inmune en esta mucosa (Kim, 2008) El reconocimiento del ácido retinoico (RA) es a través de los receptores retinoicos (RAR) y receptores X retinoicos (RXR), que se expresan en las células linfoides asociadas a la mucosa y otras células epiteliales.…”