<i>Leishmania mexicana</i> amastigotes inhibit p38 and JNK and activate PI3K/AKT: role in the inhibition of apoptosis of dendritic cells

Vázquez-López, Rosalino; Argueta, Jesús; Wilkins‐Rodríguez, Arturo A.; Escalona‐Montaño, Alma Reyna; Aguirre-Garcı́a, Marı́a Magdalena; Gutiérrez‐Kobeh, Laila

doi:10.1111/pim.12275

Cited by 19 publications

(29 citation statements)

References 57 publications

(90 reference statements)

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“…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: 92%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 92%

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

et al. 2016

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“…Indeed, DCs infected with L. mexicana amastigotes decreased the phosphorylation of MAP kinase p38 and JNK, causing a decreased DNA fragmentation in the camptothecin stimulated DCs. L. mexicana amastigotes activated antiapoptotic pathways, such as PI3K and AKT, allowing the inhibition of infected DCs’ cell death ( 50 ). The opposite effect was observed with the bacteria Brucella abortus that induced apoptosis and necrosis of murine DCs.…”

Section: Discussionmentioning

confidence: 99%

Leishmania infantum and Leishmania braziliensis: Differences and Similarities to Evade the Innate Immune System

et al. 2016

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Visceral leishmaniasis is a severe form of the disease, caused by Leishmania infantum in the New World. Patients present an anergic immune response that favors parasite establishment and spreading through tissues like bone marrow and liver. On the other hand, Leishmania braziliensis causes localized cutaneous lesions, which can be self-healing in some individuals. Interactions between host and parasite are essential to understand disease pathogenesis and progression. In this context, dendritic cells (DCs) act as essential bridges that connect innate and adaptive immune responses. In this way, the aim of this study was to compare the effects of these two Leishmania species, in some aspects of human DCs’ biology for better understanding of the evasion mechanisms of Leishmania from host innate immune response. To do so, DCs were obtained from monocytes from whole peripheral blood of healthy volunteer donors and from those infected with L. infantum or L. braziliensis for 24 h. We observed similar rates of infection (around 40%) as well as parasite burden for both Leishmania species. Concerning surface molecules, we observed that both parasites induced CD86 expression when DCs were infected for 24 h. On the other hand, we detected a lower surface expression of CD209 in the presence of both L. braziliensis and L. infantum, but only the last one promoted the survival of DCs after 24 h. Therefore, DCs infected by both Leishmania species showed a higher expression of CD86 and a decrease of CD209 expression, suggesting that both enter DCs through CD209 molecule. However, only L. infantum had the ability to inhibit DC apoptotic death, as an evasion mechanism that enables its spreading to organs like bone marrow and liver. Lastly, L. braziliensis was more silent parasite, once it did not inhibit DC apoptosis in our in vitro model.

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“…This led to the suppression of iNOS transcription and consequently NO wasn’t produced in response to LPS in L. amazonensis infection. In another study, Vázquez-López et al (2015)(15) showed the effects of activation of PKB/Akt by Leishmania infection wasn’t limited only to macrophage infections. They showed that in dendritic cells as well, L. mexicana parasites activate PKB/Akt to promote cell survival in response otherwise potent apoptotic inducers, while suppressing the MAP Kinase p38 and JNK.…”

Section: Pi3k Signaling In Leishmania Infectionsmentioning

confidence: 99%

PI3K signaling in Leishmania infections

Kima

2016

Cellular Immunology

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PI3K signaling plays a role in the host response to Leishmania infections. At the cellular level PI3K signaling is engaged by the parasite to control several cellular processes, which ensures parasite persistence. At the systemic level, there is evidence that recruitment of regulatory cells into lesions is impaired in the absence of robust PI3K signaling. In this mini-review the more recent studies that investigated the roles of PI3K signaling in Leishmania infections are discussed.

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Leishmania mexicana amastigotes inhibit p38 and JNK and activate PI3K/AKT: role in the inhibition of apoptosis of dendritic cells

Cited by 19 publications

References 57 publications

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

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

Leishmania infantum and Leishmania braziliensis: Differences and Similarities to Evade the Innate Immune System

PI3K signaling in Leishmania infections

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