Myeloid Cell IL-10 Production in Response to Leishmania Involves Inactivation of Glycogen Synthase Kinase-3β Downstream of Phosphatidylinositol-3 Kinase

Nandan, Devki; Oliveira, Carolina Camargo de; Moeenrezakhanlou, Alireza; López, Martín; Silverman, Judith M.; Subek, Jennifer; Reiner, Neil E.

doi:10.4049/jimmunol.1100076

Cited by 58 publications

(56 citation statements)

References 63 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, patients with active VL disease present high levels of IFN-g and IL-12p70 that are concomitantly detected with elevated IL-10 production (2, 23, 28). Among its cellular sources, IL-10 of myeloid origin has been long associated with disease progression (29)(30)(31). In this study, we demonstrate that the secreted IL-10 from infected DCs impaired to some extent the development of an adaptive response by decreasing the activation and proliferation of Ag-specific CD4 + T cells.…”

Section: Discussionmentioning

confidence: 57%

Leishmania-Infected MHC Class IIhigh Dendritic Cells Polarize CD4+ T Cells toward a Nonprotective T-bet+ IFN-γ+ IL-10+ Phenotype

Resende

Moreira

Augusto

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

A differential behavior among infected and bystander dendritic cells (DCs) has been explored in different infection models. We have analyzed both populations sorted on contact with visceral Leishmania infantum on a susceptible mice model evaluating the subsequent repercussions on adaptive immune response. Our results demonstrate a clear dichotomy between the immunomodulatory abilities of bystander and infected DCs. The bystander population presents increased levels of IL-12p40 and costimulatory molecules being capable to induce CD4+ T cell activation with immune protective capabilities. In contrast, infected DCs, which express lower costimulatory molecules and higher levels of IL-10, promote the development of Leishmania Ag-specific, nonprotective T-bet+IFN-γ+IL-10+ CD4+ T cells with an effector phenotype. This specific polarization was found to be dependent on IL-12p70. Splenic infected DCs recovered from chronic infected animals are similarly capable to polarize ex vivo syngeneic naive CD4+ T cells toward a T-bet+IFN-γ+IL-10+ phenotype. Further analysis revealed that only MHC class IIhigh–infected DCs were responsible for this polarization. The adoptive transfer of such polarized CD4+ T cells facilitates visceral leishmaniasis in BALB/c mice in a clear contrast with their counterpart generated with bystander DCs that significantly potentiate protection. Further, we demonstrated that CD4+ T cells primed by infected DCs in an IL-10 free system, thus deprived of T-bet+IFN-γ+IL-10+ population, restore the immune response and reduce parasite load, supporting a deleterious role of IFN-γ+IL-10+ T cells in the maintenance of infection. Overall, our results highlight novel subversion mechanisms by which nonprotective T-bet+IFN-γ+IL-10+ T cells are associated with chronicity and prolonged parasite persistence.

show abstract

Section: Discussionmentioning

confidence: 57%

Leishmania-Infected MHC Class IIhigh Dendritic Cells Polarize CD4+ T Cells toward a Nonprotective T-bet+ IFN-γ+ IL-10+ Phenotype

Resende

Moreira

Augusto

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…GR␤ overexpression resulted in a significant decrease in the levels of phosphorylation of serine 9 in GSK3␤, which increases its' activity. The decrease in GSK3␤ phosphorylation could be due to the lower Akt2 levels observed in the liver of GR␤ overexpressing mice, as previous studies have demonstrated the regulation of GSK3␤ phosphorylation by the Akt pathway (59,60).…”

Section: Discussionmentioning

confidence: 82%

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Marino

Stechschulte

Stec

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Joel GottesfeldGlucocorticoids (GCs) regulate energy supply in response to stress by increasing hepatic gluconeogenesis during fasting. Long-term GC treatment induces hepatic steatosis and weight gain. GC signaling is coordinated via the GC receptor (GR) GR␣, as the GR␤ isoform lacks a ligand-binding domain. The roles of the GR isoforms in the regulation of lipid accumulation is unknown. The purpose of this study was to determine whether GR␤ inhibits the actions of GCs in the liver, or enhances hepatic lipid accumulation. We show that GR␤ expression is increased in adipose and liver tissues in obese high-fat fed mice. Adenovirus-mediated delivery of hepatic GR␤ overexpression (GR␤-Ad) resulted in suppression of gluconeogenic genes and hyperglycemia in mice on a regular diet. Furthermore, GR␤-Ad mice had increased hepatic lipid accumulation and serum triglyceride levels possibly due to the activation of NF-B signaling and increased tumor necrosis factor ␣ (TNF␣) and inducible nitric-oxide synthase expression, indicative of enhanced M1 macrophages and the development of steatosis. Consequently, GR␤-Ad mice had increased glycogen synthase kinase 3␤ (GSK3␤) activity and reduced hepatic PPAR␣ and fibroblast growth factor 21 (FGF21) expression and lower serum FGF21 levels, which are two proteins known to increase during fasting to enhance the burning of fat by activating the ␤-oxidation pathway. In conclusion, GR␤ antagonizes the GC-induced signaling during fasting via GR␣ and the PPAR␣-FGF21 axis that reduces fat burning. Furthermore, hepatic GR␤ increases inflammation, which leads to hepatic lipid accumulation.

show abstract

“…Moreover, a significant increase in host cell apoptosis and mitochondrial membrane permeabilization upon AKT inactivation in H 2 O 2 -treated infected cells further emphasize on its bi-functional role which are in line with independent observations made by other groups. 4,5,30,31 GSK-3β was found to be inhibited by activation of AKT in L. donovani-infected condition as upon use of dominant negative AKT, phosphorylation-mediated inhibition of GSK-3β was not seen. As GSK-3β is known to inhibit or induce apoptosis depending on the stimulus, 32 we transfected cells with constitutively active GSK-3β constructs which in infection resulted in significant drop in parasite burden and anti-inflammatory responses while increasing the overall proinflammatory responses and mitochondrial membrane permeabilization, indicating that GSK-3β works as a pro-apoptotic protein in Leishmania infection.…”

Section: Discussionmentioning

confidence: 91%

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

et al. 2016

View full text Add to dashboard Cite

In order to establish infection, intra-macrophage parasite Leishmania donovani needs to inhibit host defense parameters like inflammatory cytokine production and apoptosis. In the present study, we demonstrate that the parasite achieves both by exploiting a single host regulator AKT for modulating its downstream transcription factors, β-catenin and FOXO-1. L. donovaniinfected RAW264.7 and bone marrow-derived macrophages (BMDM) treated with AKT inhibitor or dominant negative AKT constructs showed decreased anti-inflammatory cytokine production and increased host cell apoptosis resulting in reduced parasite survival. Infection-induced activated AKT triggered phosphorylation-mediated deactivation of its downstream target, GSK-3β. Inactivated GSK-3β, in turn, could no longer sequester cytosolic β-catenin, an anti-apoptotic transcriptional regulator, as evidenced from its nuclear translocation during infection. Constitutively active GSK-3β-transfected L. donovani-infected cells mimicked the effects of AKT inhibition and siRNA-mediated silencing of β-catenin led to disruption of mitochondrial potential along with increased caspase-3 activity and IL-12 production leading to decreased parasite survival. In addition to activating antiapoptotic β-catenin, phospho-AKT inhibits activation of FOXO-1, a pro-apoptotic transcriptional regulator. Nuclear retention of FOXO-1, inhibited during infection, was reversed when infected cells were transfected with dominant negative AKT constructs. Overexpression of FOXO-1 in infected macrophages not only documented increased apoptosis but promoted enhanced TLR4 expression and NF-κB activity along with an increase in IL-1β and decrease in IL-10 secretion. In vivo administration of AKT inhibitor significantly decreased liver and spleen parasite burden and switched cytokine balance in favor of host. In contrast, GSK-3β inhibitor did not result in any significant change in infectivity parameters. Collectively our findings revealed that L. donovani triggered AKT activation to regulate GSK-3β/β-catenin/FOXO-1 axis, thus ensuring inhibition of both host cell apoptosis and immune response essential for its intra-macrophage survival.

show abstract

Myeloid Cell IL-10 Production in Response to Leishmania Involves Inactivation of Glycogen Synthase Kinase-3β Downstream of Phosphatidylinositol-3 Kinase

Cited by 58 publications

References 63 publications

Leishmania-Infected MHC Class IIhigh Dendritic Cells Polarize CD4+ T Cells toward a Nonprotective T-bet+ IFN-γ+ IL-10+ Phenotype

Leishmania-Infected MHC Class IIhigh Dendritic Cells Polarize CD4+ T Cells toward a Nonprotective T-bet+ IFN-γ+ IL-10+ Phenotype

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

Contact Info

Product

Resources

About