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Lymphotoxin, but not TNF, is required for prion invasion of lymph nodes.

ABSTRACT: Neuroinvasion and subsequent destruction of the central nervous system by prions are typically preceded by a colonization phase in lymphoid organs. An important compartment harboring prions in lymphoid tissue is the follicular dendritic cell (FDC), which requires both tumor necrosis factor receptor 1 (TNFR1) and lymphotoxin ? receptor (LT?R) signaling for maintenance. However, prions are still detected in TNFR1?/? lymph nodes despite the absence of mature FDCs. Here we show that TNFR1-independent prion accumulation in lymph nodes depends on LT?R signaling. Loss of LT?R signaling, but not of TNFR1, was concurrent with the dedifferentiation of high endothelial venules (HEVs) required for lymphocyte entry into lymph nodes. Using luminescent conjugated polymers for histochemical PrP(Sc) detection, we identified PrP(Sc) deposits associated with HEVs in TNFR1?/? lymph nodes. Hence, prions may enter lymph nodes by HEVs and accumulate or replicate in the absence of mature FDCs.

SUBMITTER: O'Connor T

PROVIDER: S-EPMC3415451 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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Lymphotoxin, but not TNF, is required for prion invasion of lymph nodes.

O'Connor Tracy T Frei Nathalie N Sponarova Jana J Schwarz Petra P Heikenwalder Mathias M Aguzzi Adriano A

PLoS pathogens 20120809 8

Neuroinvasion and subsequent destruction of the central nervous system by prions are typically preceded by a colonization phase in lymphoid organs. An important compartment harboring prions in lymphoid tissue is the follicular dendritic cell (FDC), which requires both tumor necrosis factor receptor 1 (TNFR1) and lymphotoxin β receptor (LTβR) signaling for maintenance. However, prions are still detected in TNFR1⁻/⁻ lymph nodes despite the absence of mature FDCs. Here we show that TNFR1-independen ...[more]

PMID: 22912582

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Project description:While Lymphotoxin ? (TNF-?), a product of lymphocytes, is known to play a pivotal role in inflammatory joint environment, resveratrol has been shown to possess anti-inflammatory and chondroprotective effects via activation of the histondeacetylase Sirt1. Whether TNF-? induction of inflammatory pathways in primary human chondrocytes (PCH) can be modulated by resveratrol, was investigated. Monolayer and alginate cultures of PCH were treated with TNF-?, anti-TNF-?, nicotinamide (NAM), antisense oligonucleotides against Sirt1 (Sirt1-ASO) and/or resveratrol and co-cultured with T-lymphocytes. We found that resveratrol suppressed, similar to anti-TNF-?, TNF-?-induced increased adhesiveness in an inflammatory microenvironment of T-lymphocytes and PCH. In contrast, knockdown of Sirt1 by mRNA abolished the inhibitory effects of resveratrol on the TNF-?-induced adhesiveness, suggesting the essential role of this enzyme for resveratrol-mediated anti-inflammatory signaling. Similar results were obtained in PCH stimulated with TNF-?. Sirt1-ASO, NAM or TNF-?, similar to T-lymphocytes induced inflammatory microenvironment by down-regulation of cartilage-specific proteins, Sox9, Ki67 and enhanced NF-?B-regulated gene products involved in inflammatory and degradative processes in cartilage (MMP-9/-13, COX-2, caspase-3), NF-?B activation and its translocation to the nucleus. Moreover, resveratrol reversed the TNF-?-, NAM-, T-lymphocytes-induced up-regulation of various NF-?B-regulated gene products. Down-regulation of Sirt1 by mRNA interference abrogated the effect of resveratrol on TNF-?-induced effects. Ultrastructural and cell viability assay investigations revealed that resveratrol revoked TNF-?-induced dose-dependent degradative/apoptotic morphological changes, cell viability and proliferation in PCH. Taken together, suppression of TNF-?-induced inflammatory microenvironment in PCH by resveratrol/Sirt1 might be a novel therapeutic approach for targeting inflammation during rheumatoid arthritis.

Dataset Information

Lymphotoxin, but not TNF, is required for prion invasion of lymph nodes.

Publications

Lymphotoxin, but not TNF, is required for prion invasion of lymph nodes.

Similar Datasets

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