all-trans-Retinoic acid improves immunocompetence in a murine model of lipopolysaccharide-induced immunosuppression

Abstract

Secondary infections due to post-sepsis immunosuppression are a major cause of death in patients with sepsis. Strategies aimed at restoring immune functions offer a new perspective in the treatment of sepsis. In the present study, we used LPS (lipopolysaccharide)-immunosuppressed mice to analyse the effects of ATRA (all-trans retinoic acid) on different immune parameters. The IS (immunocompromised) group had decreased lymphocyte and increased MDSC (myeloid-derived suppressor cell) counts in lymph nodes. They also had an impaired in vitro T-cell proliferation, mediated by MDSCs. ATRA administration restored T-cell proliferation, which was associated with a decreased number of live MDSCs. The IS group treated with ATRA had an increased number of CD4+ and CD8+ T-cells. ATRA partially improved the primary humoral immune response, even when immunosuppression was established first and ATRA was administered subsequently. Our results demonstrate that ATRA restores immunocompetence by modulating the number of leucocytes and the survival of MDSCs, and thus represents an additional potential strategy in the treatment of the immunosuppressive state of sepsis.

Immature myeloid Gr-1+ CD11b+ cells from lipopolysaccharide-immunosuppressed mice acquire inhibitory activity in the bone marrow and migrate to lymph nodes to exert their suppressive function

“…Although both subsets can potentially suppress lymphocyte proliferation, they may not always be involved, depending on the context and the pathology in question. Considering this, and taking into account that we have previously described an increase in both subsets in LNs of IS mice [15], we determined, in the context of LPS-induced immunosuppression, whether both subsets acquired their inhibitory capacity in the BM. As shown in Figure 6(A), both purified Gr-1 high and Gr-1 low subsets from the BM of IS mice inhibited T-cell proliferation.…”

“…In mice repetitive inoculation of LPS induces a strong immunosuppressive state which is used as a model to study the immunosuppression that patients may develop after an episode of sepsis (late sepsis immunosuppression) [14,15]. Using this model we first assessed whether BM cells from IS mice expressed an inhibitory activity.…”

“…This fact was associated with an increase in MDSCs (Gr-1 + CD11b + ). Moreover, decreasing the number of viable MDSCs with all-trans-retinoic acid treatment improved immunocompetence, restoring T-cell proliferation, antibody production and normal lymphocyte numbers [15]. These data clearly connect suppressive Gr-1 + CD11b + cells and failure of immunocompetence.…”

“…Experimentally, repetitive inoculation of increasing doses of LPS into mice induces derangements in the inflammatory response and a state of adaptive immunosuppression [10,14,15].…”

MicroRNA 21 (miR-21) and miR-181b Couple with NFI-A To Generate Myeloid-Derived Suppressor Cells and Promote Immunosuppression in Late Sepsis

“…Interestingly, recent studies reported that factors that eliminate MDSCs can overcome immune suppression and improve the immune response. For example, all-trans-retinoic acid, which promotes myeloid differentiation, has been shown to reduce MDSCs and to improve immunocompetence in tumor-bearing mice (19) and in mice with lipopolysaccharide (LPS)-induced immune suppression (20). We (8) and others (21,22) have shown that MDSCs dramatically expand in the mouse bone marrow during the course of polymicrobial sepsis.…”