Carbohydrate Oxidation Acidifies Endosomes, Regulating Antigen Processing and TLR9 Signaling

Lewis, Colleen J.; Cobb, Brian A.

doi:10.4049/jimmunol.0903168

Cited by 19 publications

(18 citation statements)

References 50 publications

(63 reference statements)

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“…In fact, CGD favors vesicular acidification and increased conventional antigen proteolysis [35]. In sharp contrast, GlyAg processing is dependent upon a neutral pH and acidification stops GlyAg processing in cells [40]. As a result, one might expect the CGD cells to process GlyAg less than the WT counterparts due to increased acidification, yet we observed the opposite.…”

Section: Discussionmentioning

confidence: 74%

Adaptive immune defects against glycoantigens in chronic granulomatous disease via dysregulated nitric oxide production

Lewis

Cobb

2011

Eur J Immunol

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Chronic granulomatous disease (CGD) is a primary immunodeficiency defined by mutations in the NADPH oxidase complex leading to reduced superoxide production, increased susceptibility to infection, chronic inflammation, and recurring abscess and granuloma formation. Here, we found that CGD mice were hyperresponsive to abscess-inducing T-cell-dependent carbohydrate antigens (glycoantigens) due to a ten-fold increase in NO production within APCs, which is known to be necessary for glycoantigen presentation on MHC class II. CGD mice exhibited increased Th1 pro-inflammatory T-cell responses in vitro and in vivo, characterized by more severe abscess pathology. This phenotype was also seen in WT animals following adoptive transfer of neutrophil-depleted APCs from CGD animals, demonstrating that this phenotype was independent of neutrophil and T-cell defects. Finally, pharmacological attenuation of NO production to WT levels in vivo reduced abscess incidence and severity in CGD without overt increases in inflammation or the ability to clear infection, suggesting a potential new treatment option for early stage CGD-associated infections.

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Section: Discussionmentioning

confidence: 74%

Adaptive immune defects against glycoantigens in chronic granulomatous disease via dysregulated nitric oxide production

Lewis

Cobb

2011

Eur J Immunol

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“…In order to confirm the causal relationship between NO and suppression, we examined MDSC suppressive activity using the iNOS inhibitor 1400W (40,41). Directly inhibiting NO production (Fig.…”

Section: Resultsmentioning

confidence: 99%

Neutrophils Confer T Cell Resistance to Myeloid-Derived Suppressor Cell–Mediated Suppression To Promote Chronic Inflammation

Ryan

Johnson

Cobb

2013

The Journal of Immunology

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Low-grade chronic inflammation can persist in aging humans unnoticed for years or even decades, inflicting continuous damage that can culminate later in life as organ dysfunction, physical frailty, and some of the most prominent debilitating and deadly age-associated diseases, including rheumatoid arthritis, diabetes, heart disease, and cancer. Despite the near universal acceptance of these associations, the mechanisms underlying unresolved inflammation remain poorly understood. Here we describe a novel inducible method to examine systemic chronic inflammation using susceptible animal models. Induced inflammation results in unresolved innate cellular responses and persistence of the same serum pro-inflammatory molecules used as diagnostic biomarkers and therapeutic targets for chronic inflammation in humans. Surprisingly, we found long-term persistence of an inflammation-associated neutrophil cell population constitutively producing the pro-inflammatory IFNγ cytokine, which until now has only been detected transiently in acute inflammatory responses. Interestingly, these cells appear to confer T cell resistance to the otherwise potent anti-inflammatory function of myeloid-derived suppressor cells (MDSC), revealing a novel mechanism for the maintenance of chronic inflammatory responses over time. This discovery represents an attractive target to resolve inflammation and prevent the inflammation-induced pathologies that are of critical concern for the wellbeing of the aging population.

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“…Because successful cleavage of TLR9 required an acidic compartment, it is tempting to speculate that uptake of Af conidia and subsequent phagosomal acidification (41) may facilitate cleavage and retention in the phagosome. A recent report indicated that acidification induced by carbohydrates from encapsulated microbes facilitated TLR9 signaling (49). TLR9 recruitment, cleavage and retention at the fungal phasosome may be prerequisite steps for successful signaling to TLR9 ligands that are released during phagosomal processing.…”

Section: Discussionmentioning

confidence: 99%

TLR9 Is Actively Recruited to Aspergillus fumigatus Phagosomes and Requires the N-Terminal Proteolytic Cleavage Domain for Proper Intracellular Trafficking

Kasperkovitz

Cardenas

Vyas

2010

The Journal of Immunology

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Toll-like receptor 9 (TLR9) recognizes unmethylated CpG DNA and induces innate immune responses. TLR9 activation is a multistep process requiring proteolytic cleavage and trafficking to endolysosomal compartments for ligand-induced signaling. However, the rules that govern the dynamic subcellular trafficking for TLR9 after pathogen uptake have not been established. In this study, we demonstrate that uptake of Aspergillus fumigatus (Af) conidia induced drastic spatial redistribution of TLR9 to the phagosomal membrane of Af-containing phagosomes but not to bead-containing phagosomes in murine macrophages. Specific TLR9 recruitment to the fungal phagosome was consistent using Af spores at different germination stages and selected mutants affecting the display of antigens on the fungal cell surface. Spatiotemporal regulation of TLR9 compartmentalization to the Af phagosome was independent of TLR2, TLR4 and downstream TLR signaling. Our data demonstrate that the TLR9 N-terminal proteolytic cleavage domain was critical for successful intracellular trafficking and accumulation of TLR9 in CpG-containing compartments and Af-phagosomal membranes. Our study provides evidence for a model in which Af spore phagocytosis by macrophages specifically induces TLR9 recruitment to Af phagosomes and may thereby mediate TLR9-induced antifungal innate immune responses.

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Carbohydrate Oxidation Acidifies Endosomes, Regulating Antigen Processing and TLR9 Signaling

Abstract: Material

Cited by 19 publications

References 50 publications

Adaptive immune defects against glycoantigens in chronic granulomatous disease via dysregulated nitric oxide production

Adaptive immune defects against glycoantigens in chronic granulomatous disease via dysregulated nitric oxide production

Neutrophils Confer T Cell Resistance to Myeloid-Derived Suppressor Cell–Mediated Suppression To Promote Chronic Inflammation

TLR9 Is Actively Recruited to Aspergillus fumigatus Phagosomes and Requires the N-Terminal Proteolytic Cleavage Domain for Proper Intracellular Trafficking

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