Novel use of All-trans-Retinoic Acid in a model of Lipopolysaccharideimmunosuppression to decrease the generation of myeloid-derived suppressor cells by reducing the proliferation of CD34+ precursor cells.

MARTIRE GRECO D; RODRIGUEZ RODRIGUES, NAHUEL; LUIS A CASTILLO; MARIA BELEN VECCIONE; CAMPOS-NEBEL M; CORDOBA MORENO, MARLINA; MEISS R; VERMEULEN M; LANDONI V.I; FERNANDEZ G.C

SHOCK

LIPPINCOTT WILLIAMS & WILKINS

Lugar: Philadelphia; Año: 2017 vol. 48 p. 94 - 103

1073-2322

ABSTRACT?All-trans-retinoic acid (ATRA) is a derivative of vitamin A with antiproliferative properties. Endotoxin shock andsubsequent immunosuppression (IS) by lipopolysaccharide (LPS) stimulates myelopoiesis with expansion of myeloidderivedsuppressor cells (MDSC). Since we have previously shown that ATRA reverses the IS state by decreasing functionalMDSC, our aim was to investigate if ATRA was able to modulate MDSC generation by regulating myelopoiesis in murinehematopoietic organs. We found that ATRA administration in vivo and in vitro decreased the number of CD34þ precursorcells that were increased in IS mice. When we studied the cellular mechanisms involved, we did not find any differences inapoptosis of CD34þ precursors or in the differentiation of these cells to their mature counterparts. Surprisingly, ATRAdecreased precursor proliferation, in vitro and in vivo, as assessed by a reduction in the size and number of colony formingunits generated from CD34þ cells and by a decreased incorporation of 3H-thymidine. Moreover, ATRA administration to ISmice decreased the number of MDSC in the spleen, with a restoration of T lymphocyte proliferation and a restitution of thehistological 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 onthe improvement of immune competence. Administration of ATRA could overcome the immunosuppressive state generatedby sepsis that often leads to opportunistic life-threatening infections. Therefore, ATRA could be considered a complementarytreatment to enhance immune responses.KEYWORDS?ATRA, immunosuppression, LPS, MDSC, sepsis