title: Novel Use of All-Trans-Retinoic Acid in A Model of Lipopolysaccharide-Immunosuppression to Decrease the Generation of Myeloid-Derived Suppressor Cells by Reducing the Proliferation of CD34+ Precursor Cells.
abstract: All-trans-retinoic acid (ATRA) is a derivative of vitamin A with antiproliferative properties. Endotoxin shock and subsequent immunosuppression (IS) by lipopolysaccharide (LPS) stimulates myelopoiesis with expansion of myeloid-derived suppressor cells (MDSC). Since we have previously shown that ATRA reverses the IS state by decreasing functional MDSC, our aim was to investigate if ATRA was able to modulate MDSC generation by regulating myelopoiesis in murine hematopoietic organs. We found that ATRA administration in vivo and in vitro decreased the number of CD34+ precursor cells that were increased in IS mice. When we studied the cellular mechanisms involved, we did not find any differences in apoptosis of CD34+ precursors or in the differentiation of these cells to their mature counterparts. Surprisingly, ATRA decreased precursor proliferation, in vitro and in vivo, as assessed by a reduction in the size and number of colony forming units generated from CD34+ cells and by a decreased incorporation of H-thymidine. Moreover, ATRA administration to IS mice decreased the number of MDSC in the spleen, with a restoration of T lymphocyte proliferation and a restitution of the histological architecture. Our results indicate, for the first time, a new use of ATRA to abolish LPS-induced myelopoiesis, affecting the proliferation of precursor cells, and in consequence, decreasing MDSC generation, having a direct impact on the improvement of immune competence. Administration of ATRA could overcome the immunosuppressive state generated by sepsis that often leads to opportunistic life-threatening infections. Therefore, ATRA could be considered a complementary treatment to enhance immune responses.
authors.affiliation: *Laboratory of Physiology of Inflammatory Processes of the Institute of Experimental Medicine (IMEX-CONICET), National Academy of Medicine, Buenos Aires, Argentina †Institute for Biomedical Research in Retroviruses and AIDS (U.B.A.-CONICET), Buenos Aires, Argentina ‡Mutagenesis Laboratory, National Academy of Medicine, Buenos Aires, Argentina §Division of Experimental Pathology, National Academy of Medicine, Buenos Aires, Argentina ||Laboratory of Immunology of the Institute of Experimental Medicine (IMEX-CONICET), National Academy of Medicine, Buenos Aires, Argentina.
authors.forename: Daiana
authors.initials: D
authors.lastname: Martire-Greco
authors.forename: Nahuel
authors.initials: N
authors.lastname: Rodriguez-Rodrigues
authors.forename: Luis A
authors.initials: LA
authors.lastname: Castillo
authors.forename: María Belén
authors.initials: MB
authors.lastname: Vecchione
authors.forename: Marcelo
authors.initials: M
authors.lastname: de Campos-Nebel
authors.forename: Marlina
authors.initials: M
authors.lastname: Córdoba Moreno
authors.forename: Roberto
authors.initials: R
authors.lastname: Meiss
authors.forename: Mónica
authors.initials: M
authors.lastname: Vermeulen
authors.forename: Veronica I
authors.initials: VI
authors.lastname: Landoni
authors.forename: Gabriela C
authors.initials: GC
authors.lastname: Fernandez
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D018952:Antigens, CD34; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014212:Tretinoin