• Transl Res · May 2023

    Inhibition of PI3K/C/EBPβ axis in tolerogenic bone marrow derived dendritic cells of NOD mice promotes Th17 differentiation and diabetes development.

    • Chantal Guindi, Farhan Ullah Khan, Alexandre Cloutier, Puregmaa Khongorzul, Ahmed Aziz Raki, Simon Gaudreau, Patrick P McDonald, Denis Gris, and Abdelaziz Amrani.
    • Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada.
    • Transl Res. 2023 May 1; 255: 374937-49.

    AbstractDendritic cells (DCs) are key regulators of the adaptive immune response. Tolerogenic dendritic cells play a crucial role in inducing and maintaining immune tolerance in autoimmune diseases such as type 1 diabetes in humans as well as in the NOD mouse model. We previously reported that bone marrow-derived DCs (BM.DCs) from NOD mice, generated with a low dose of GM-CSF (GM/DCs), induce Treg differentiation and are able to protect NOD mice from diabetes. We had also found that the p38 MAPK/C/EBPβ axis is involved in regulating the phenotype, as well as the production of IL-10 and IL-12p70, by tolerogenic GM/DCs. Here, we report that the inhibition of the PI3K signaling switched the cytokine profile of GM/DCs toward Th17-promoting cytokines without affecting their phenotype. PI3K inhibition abrogated the production of IL-10 by GM/DCs, whereas it enhanced their production of IL-23 and TGFβ. Inhibition of PI3K signaling in tolerogenic GM/DCs also induced naive CD4+ T cells differentiation toward Th17 cells. Mechanistically, PI3K inhibition increased the DNA-binding activity of C/EBPβ through a GSK3-dependent pathway, which is important to maintain the semimature phenotype of tolerogenic GM/DCs. Furthermore, analysis of C/EBPβ-/- GM/DCs demonstrated that C/EBPβ is required for IL-23 production. Of physiological relevance, the level of protection from diabetes following transfusion of GM/DCs into young NOD mice was significantly reduced when NOD mice were transfused with GM/DCs pretreated with a PI3K inhibitor. Our data suggest that PI3K/C/EBPβ signaling is important in controlling tolerogenic function of GM/DCs by limiting their Th17-promoting cytokines.Copyright © 2022 Elsevier Inc. All rights reserved.

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