PMID- 36400308
OWN - NLM
STAT- MEDLINE
DCOM- 20230410
LR  - 20230505
IS  - 1878-1810 (Electronic)
IS  - 1878-1810 (Linking)
VI  - 255
DP  - 2023 May
TI  - Inhibition of PI3K/C/EBPbeta axis in tolerogenic bone marrow-derived dendritic cells 
      of NOD mice promotes Th17 differentiation and diabetes development.
PG  - 37-49
LID - S1931-5244(22)00248-1 [pii]
LID - 10.1016/j.trsl.2022.11.005 [doi]
AB  - Dendritic 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/EBPbeta 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 TGFbeta. 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/EBPbeta 
      through a GSK3-dependent pathway, which is important to maintain the semimature 
      phenotype of tolerogenic GM/DCs. Furthermore, analysis of C/EBPbeta(-/-) GM/DCs 
      demonstrated that C/EBPbeta 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/EBPbeta 
      signaling is important in controlling tolerogenic function of GM/DCs by limiting 
      their Th17-promoting cytokines.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Guindi, Chantal
AU  - Guindi C
AD  - Department of Pediatrics, Immunology Division, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, 
      Quebec, Canada.
FAU - Khan, Farhan Ullah
AU  - Khan FU
AD  - Department of Pediatrics, Immunology Division, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, 
      Quebec, Canada.
FAU - Cloutier, Alexandre
AU  - Cloutier A
AD  - Department of Pediatrics, Immunology Division, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, 
      Quebec, Canada.
FAU - Khongorzul, Puregmaa
AU  - Khongorzul P
AD  - Department of Pediatrics, Immunology Division, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, 
      Quebec, Canada.
FAU - Raki, Ahmed Aziz
AU  - Raki AA
AD  - Department of Pediatrics, Immunology Division, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, 
      Quebec, Canada.
FAU - Gaudreau, Simon
AU  - Gaudreau S
AD  - Department of Pediatrics, Immunology Division, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, 
      Quebec, Canada.
FAU - McDonald, Patrick P
AU  - McDonald PP
AD  - Department of Pediatrics, Immunology Division, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, 
      Quebec, Canada.
FAU - Gris, Denis
AU  - Gris D
AD  - Department of Pediatrics, Immunology Division, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, 
      Quebec, Canada.
FAU - Amrani, Abdelaziz
AU  - Amrani A
AD  - Department of Pediatrics, Immunology Division, Faculty of Medicine and Health 
      Sciences, Universite de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, 
      Quebec, Canada. Electronic address: abdelaziz.amrani@usherbrooke.ca.
LA  - eng
GR  - MOP-300762/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221115
PL  - United States
TA  - Transl Res
JT  - Translational research : the journal of laboratory and clinical medicine
JID - 101280339
RN  - 130068-27-8 (Interleukin-10)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-23)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - Mice, Inbred NOD
MH  - *Interleukin-10
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Th17 Cells/metabolism
MH  - Bone Marrow
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - T-Lymphocytes, Regulatory
MH  - Cell Differentiation
MH  - Cytokines/metabolism
MH  - Immune Tolerance
MH  - Dendritic Cells/metabolism
MH  - Interleukin-23/metabolism
MH  - *Diabetes Mellitus/metabolism
EDAT- 2022/11/19 06:00
MHDA- 2023/04/10 06:42
CRDT- 2022/11/18 19:34
PHST- 2022/04/14 00:00 [received]
PHST- 2022/11/01 00:00 [revised]
PHST- 2022/11/08 00:00 [accepted]
PHST- 2023/04/10 06:42 [medline]
PHST- 2022/11/19 06:00 [pubmed]
PHST- 2022/11/18 19:34 [entrez]
AID - S1931-5244(22)00248-1 [pii]
AID - 10.1016/j.trsl.2022.11.005 [doi]
PST - ppublish
SO  - Transl Res. 2023 May;255:37-49. doi: 10.1016/j.trsl.2022.11.005. Epub 2022 Nov 
      15.