Abstract
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/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.
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References
- Dendritic cells as inducers of peripheral tolerance.Trends Immunol. 2017; 38: 793-804
- Natural and induced tolerogenic dendritic cells.J Immunol. 2020; 204: 733-744
- Dendritic cells in the regulation of immunity and inflammation.Semin Immunol. 2018; 35: 3-11
- Costimulatory molecules and immune checkpoints are differentially expressed on different subsets of dendritic cells.Front Immunol. 2019; 10: 1325
- GM-CSF induces bone marrow precursors of NOD mice to skew into tolerogenic dendritic cells that protect against diabetes.Cell Immunol. 2010; 265: 31-36
- The importance of dendritic cells in maintaining immune tolerance.J Immunol. 2017; 198: 2223-2231
- Therapeutic effect of tolerogenic dendritic cells in established collagen-induced arthritis is associated with a reduction in Th17 responses.Arthritis Rheum. 2010; 62: 3656-3665
- Optimal tolerogenic dendritic cells in type 1 diabetes (T1D) therapy: what can we learn from non-obese diabetic (NOD) mouse models?.Front Immunol. 2019; 10: 967
- Insulin-dependent diabetes mellitus.Cell. 1996; 85: 291-297
- The role of NOD mice in type 1 diabetes research: lessons from the past and recommendations for the future.Front Endocrinol (Lausanne). 2018; 9: 51
- The heterogeneous pathogenesis of type 1 diabetes mellitus.Nat Rev Endocrinol. 2019; 15: 635-650
- Th17 cells in type 1 diabetes: role in the pathogenesis and regulation by gut microbiome.Mediators Inflamm. 2015; 2015638470
- Elevated NF-kappaB activation in nonobese diabetic mouse dendritic cells results in enhanced APC function.J Immunol. 2002; 168: 188-196
- Dendritic cells from nonobese diabetic mice exhibit a defect in NF-kappa B regulation due to a hyperactive I kappa B kinase.J Immunol. 2001; 167: 1461-1468
- Dendritic cell subsets in type 1 diabetes: friend or foe?.Front Immunol. 2013; 4: 415
- The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.Cell. 2006; 126: 1121-1133
- The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.Nat Immunol. 2008; 9: 641-649
- IL-17 family cytokines and the expanding diversity of effector T cell lineages.Annu Rev Immunol. 2007; 25: 821-852
- Development, cytokine profile and function of human interleukin 17-producing helper T cells.Nat Immunol. 2007; 8: 950-957
- TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity. 2006; 24: 179-189
- IL-23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin.Eur J Immunol. 2006; 36: 216-223
- Preventative role of interleukin-17 producing regulatory T helper type 17 (Treg 17) cells in type 1 diabetes in non-obese diabetic mice.Clin Exp Immunol. 2015; 182: 261-269
- Insight into non-pathogenic Th17 cells in autoimmune diseases.Front Immunol. 2018; 9: 1112
- The potential pathogenic role of IL-17/Th17 cells in both type 1 and type 2 diabetes mellitus.Biomed Pharmacother. 2018; 101: 287-292
- Th17 cells in type 1 diabetes.Cell Immunol. 2012; 280: 16-21
- Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice.Diabetes. 2009; 58: 1302-1311
- Innocuous IFNgamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production.J Exp Med. 2008; 205: 207-218
- Differential role of NF-kappaB, ERK1/2 and AP-1 in modulating the immunoregulatory functions of bone marrow-derived dendritic cells from NOD mice.Cell Immunol. 2012; 272: 259-268
- Role of the p38 MAPK/C/EBPbeta pathway in the regulation of phenotype and IL-10 and IL-12 production by tolerogenic bone marrow-derived dendritic cells.Cells. 2018; 7: 256https://doi.org/10.3390/cells7120256
- Effects of Artesunate on chondrocyte proliferation, apoptosis and autophagy through the PI3K/AKT/mTOR signaling pathway in rat models with rheumatoid arthritis.Biomed Pharmacother. 2018; 102: 1209-1220
- Cystic fibrosis transmembrane conductance regulator ameliorates lipopolysaccharide-induced acute lung injury by inhibiting autophagy through PI3K/AKT/mTOR pathway in mice.Respir Physiol Neurobiol. 2020; 273103338
- PI3K-mediated negative feedback regulation of IL-12 production in DCs.Nat Immunol. 2002; 3: 875-881
- PI3K activity in dendritic cells exerts paradoxical effects during autoimmune inflammation.Mol Immunol. 2019; 111: 32-42
- Elucidating the role of Ezh2 in tolerogenic function of NOD bone marrow-derived dendritic cells expressing constitutively active Stat5b.Int J Mol Sci. 2020; 21: 6453https://doi.org/10.3390/ijms21186453
- Insulin suppresses transactivation by CAAT/enhancer-binding proteins beta (C/EBPbeta). Signaling to p300/CREB-binding protein by protein kinase B disrupts interaction with the major activation domain of C/EBPbeta.J Biol Chem. 2001; 276: 8516-8523
- Insulin activates CCAAT/enhancer binding proteins and proinflammatory gene expression through the phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells.J Biol Chem. 2002; 277: 36631-36639
- Targeted regulation of PI3K/Akt/mTOR/NF-kappaB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy.Anticancer Agents Med Chem. 2013; 13: 1002-1013
- Soyasaponins can blunt inflammation by inhibiting the reactive oxygen species-mediated activation of PI3K/Akt/NF-kB pathway.PLoS One. 2014; 9e107655
- Dendritic cell development and survival require distinct NF-kappaB subunits.Immunity. 2002; 16: 257-270
- Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation.Nature. 2000; 406: 86-90
- GSK3: a kinase balancing promotion and resolution of inflammation.Cells. 2020; 9: 820https://doi.org/10.3390/cells9040820
- Epidermal growth factor-stimulated extravillous cytotrophoblast motility is mediated by the activation of PI3-K, Akt and both p38 and p42/44 mitogen-activated protein kinases.Hum Reprod. 2008; 23: 1733-1741
- Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation.Science. 2008; 320: 667-670
- Induction and molecular signature of pathogenic TH17 cells.Nat Immunol. 2012; 13: 991-999
- Innate immune recognition of infected apoptotic cells directs T(H)17 cell differentiation.Nature. 2009; 458: 78-82
- Sodium chloride drives autoimmune disease by the induction of pathogenic T17 cells.Nature. 2013; 496: 518-522
- Inhibition of delta-like ligand 4 decreases Th1/Th17 response in a mouse model of multiple sclerosis.Neurosci Lett. 2013; 541: 161-166
- Loss of the balance between CD4Foxp3 regulatory T cells and CD4IL17A Th17 cells in patients with type 1 diabetes.Hum Immunol. 2013; 74: 701-707
- Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice.J Clin Invest. 2009; 119: 565-572
- Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells.Eur J Immunol. 2009; 39: 216-224
- Single-cell genomics unveils critical regulators of Th17 cell pathogenicity.Cell. 2015; 163: 1400-1412
- Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells.Indian J Med Res. 2013; 138: 591-594
- Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity.J Clin Invest. 2015; 125: 2211-2219
- Adrenergic beta2 receptor activation stimulates anti-inflammatory properties of dendritic cells in vitro.PLoS One. 2014; 9: e85086
- Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE.Eur J Immunol. 2012; 42: 2555-2563
- NF-kappaB, p38 MAPK, ERK1/2, mTOR, STAT3 and increased glycolysis regulate stability of paricalcitol/dexamethasone-generated tolerogenic dendritic cells in the inflammatory environment.Oncotarget. 2015; 6: 14123-14138
- Paricalcitol (19-nor-1,25-dihydroxyvitamin D2) and calcitriol (1,25-dihydroxyvitamin D3) exert potent immunomodulatory effects on dendritic cells and inhibit induction of antigen-specific T cells.Clin Immunol. 2009; 133: 69-77
- beta-Glucan enhances cytotoxic T lymphocyte responses by activation of human monocyte-derived dendritic cells via the PI3K/AKT pathway.Hum Immunol. 2015; 76: 146-154
- Regulation of dendritic cell function by insulin/IGF-1/PI3K/Akt signaling through klotho expression.J Recept Signal Transduct Res. 2017; 37: 297-303
- Vitamin D3 induces tolerance in human dendritic cells by activation of intracellular metabolic pathways.Cell Rep. 2015; 10: 711-725
- GSK3 and its interactions with the PI3K/AKT/mTOR signalling network.Adv Biol Regul. 2017; 65: 5-15
- Inhibition of GSK3 differentially modulates NF-kappaB, CREB, AP-1 and beta-catenin signaling in hepatocytes, but fails to promote TNF-alpha-induced apoptosis.Exp Cell Res. 2008; 314: 1351-1366
- TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.Nat Immunol. 2007; 8: 1390-1397
- CCAAT/Enhancer-binding protein beta promotes pathogenesis of EAE.Cytokine. 2017; 92: 24-32
- The role of C/EBP isoforms in the control of inflammatory and native immunity functions.J Biol Chem. 1998; 273: 29279-29282
- CCAAT/enhancer-binding proteins: structure, function and regulation.Biochem J. 2002; 365: 561-575
- C/EBP beta gene inactivation causes both impaired and enhanced gene expression and inverse regulation of IL-12 p40 and p35 mRNAs in macrophages.J Immunol. 2002; 168: 4055-4062
- Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer.PLoS Pathog. 2018; 14e1007001
Article info
Publication history
Published online: November 14, 2022
Accepted:
November 8,
2022
Received in revised form:
November 1,
2022
Received:
April 14,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.