Arabinosylated lipoarabinomannan (Ara-LAM) mediated intracellular mechanisms against tuberculosis infection: Involvement of protein kinase C (PKC) mediated signaling

Das, Shibali; Bhattacharjee, Oindrila; Goswami, Anupam; Pal, Nishith Kumar; Majumdar, Subrata

doi:10.1016/j.tube.2014.11.007

Cited by 11 publications

(6 citation statements)

References 39 publications

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“…This result is in contrast to non-CF monocytes where PKCδ is required for p47 phox phosphorylation (38), but correlates with a recent study showing restoration of CF macrophage microbicidal functions with OAG-mediated calcium signaling (56). Additionally, conventional PKC expression is implicated in macrophage control of intracellular pathogens such as Mycobacterium tuberculosis (57) and we now demonstrate PKC to be deficient in the handling of B. cenocepacia infection in CF MDMs, lending support to the notion of dysregulated PKC control of intracellular pathogens in CF. Our findings are consistent with an early study that showed chemiluminescent defects in PKC-mediated actions in CF neutrophils (58).…”

Section: Discussionsupporting

confidence: 69%

Human Cystic Fibrosis Macrophages Have Defective Calcium-Dependent Protein Kinase C Activation of the NADPH Oxidase, an Effect Augmented by Burkholderia cenocepacia

Assani

Shrestha

Robledo‐Avila

et al. 2017

The Journal of Immunology

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Macrophage intracellular pathogen killing is defective in cystic fibrosis (CF), despite abundant production of reactive oxygen species (ROS) in lung tissue. Burkholderia species can cause serious infection in CF and themselves affect key oxidase components in murine non-CF cells. However, it is unknown whether human CF macrophages have an independent defect in the oxidative burst and whether Burkholderia contributes to this defect in terms of assembly of the NADPH oxidase complex and subsequent ROS production. Here we analyze CF and non-CF human monocyte-derived macrophages (MDMs) for ROS production, NADPH assembly capacity, protein kinase C (PKC) expression, and calcium release in response to PMA and CF pathogens. CF MDMs demonstrate a nearly 60% reduction in superoxide production following PMA stimulation compared to non-CF MDMs. Although CF MDMs generally have increased total NADPH component protein expression, they demonstrate decreased expression of the calcium-dependent PKC conventional subclass α/β leading to reduced phosphorylation of NADPH oxidase components p47phox & p40phox in comparison to non-CF MDMs. Ingestion of B. cenocepacia independently contributes to and worsens the overall oxidative burst deficits in CF MDMs compared to non-CF MDMs. Together, these results provide evidence for inherent deficits in the CF macrophage oxidative burst due to decreased phosphorylation of NADPH oxidase cytosolic components that are augmented by Burkholderia. These findings implicate a critical role for defective macrophage oxidative responses in persistent bacterial infections in CF and create new opportunities for boosting the macrophage immune response in order to limit infection.

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Section: Discussionsupporting

confidence: 69%

Human Cystic Fibrosis Macrophages Have Defective Calcium-Dependent Protein Kinase C Activation of the NADPH Oxidase, an Effect Augmented by Burkholderia cenocepacia

Assani

Shrestha

Robledo‐Avila

et al. 2017

The Journal of Immunology

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“…cPKC activation seems to be associated with proinflammation as evident by the activation of these isoforms on coincubation with IFNγ ( 47 ). In Mycobacterium tuberculosis -infected macrophages, PKCα upregulates proinflammatory response in conjugation with TLR2 on pretreatment with arabinosylated lipoarabinomannan ( 48 ). While PKCα/β mediates CD40-induced p38MAPK phosphorylation and IL-12 expression, PKCδ and ζ inhibit it reciprocally by enhancing ERK1/2 phosphorylation and IL-10 production ( 8 ).…”

Section: Differential Pkc Isoform Regulation In Infectionmentioning

confidence: 99%

Spatio-Temporal Regulation of PKC Isoforms Imparts Signaling Specificity

et al. 2016

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“…It is noteworthy to mention that Ara-LAM works well when utilized as an immunotherapiutic agent administered 2days prior to L . donovani infection [ 18 – 20 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…In coimmunoprecipitation studies, the lysates of differently treated CD8 + T-cells were incubated with specific antibody (TLR2, MyD88). The complexes were captured with immobilized Protein A-agarose beads, washed, resolved by 10% SDS-PAGE and developed with antibodies to MyD88 and IRAK 1 to detect TLR2-MyD88, MyD88-IRAK 1 interactions [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor 2 Targeted Rectification of Impaired CD8+ T Cell Functions in Experimental Leishmania donovani Infection Reinstates Host Protection

et al. 2015

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Leishmania donovani, a protozoan parasite, causes the disease visceral leishmanisis (VL), characterized by inappropriate CD8+ T-cell activation. Therefore, we examined whether the Toll-like Receptor 2 (TLR2) ligand Ara-LAM, a cell wall glycolipid from non-pathogenic Mycobacterium smegmatis, would restore CD8+ T-cell function during VL. We observed that by efficient upregulation of TLR2 signaling-mediated NF-κB translocation and MAPK signaling in CD8+ T-cells (CD25+CD28+IL-12R+IFN-γR+), Ara-LAM triggered signaling resulted in the activation of T-bet, which in turn, induced transcription favourable histone modification at the IFN-γ, perforin, granzyme-B promoter regions in CD8+ T-cells. Thus, we conclude that Ara-LAM induced efficient activation of effector CD8+ T-cells by upregulating the expression of IFN-γ, perforin and granzyme-B in an NF-κB and MAPK induced T-bet dependent manner in VL.

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Arabinosylated lipoarabinomannan (Ara-LAM) mediated intracellular mechanisms against tuberculosis infection: Involvement of protein kinase C (PKC) mediated signaling

Cited by 11 publications

References 39 publications

Human Cystic Fibrosis Macrophages Have Defective Calcium-Dependent Protein Kinase C Activation of the NADPH Oxidase, an Effect Augmented by Burkholderia cenocepacia

Human Cystic Fibrosis Macrophages Have Defective Calcium-Dependent Protein Kinase C Activation of the NADPH Oxidase, an Effect Augmented by Burkholderia cenocepacia

Spatio-Temporal Regulation of PKC Isoforms Imparts Signaling Specificity

Toll-Like Receptor 2 Targeted Rectification of Impaired CD8+ T Cell Functions in Experimental Leishmania donovani Infection Reinstates Host Protection

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