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Lymphotoxin-alpha contributes to lymphangiogenesis.

ABSTRACT: Lymphotoxin-? (LT?), lymphotoxin-? (LT?), and tumor necrosis factor-? (TNF?) are inflammatory mediators that play crucial roles in lymphoid organ development. We demonstrate here that LT? also contributes to the function of lymphatic vessels and to lymphangiogenesis during inflammation. LT?(-/-) mice exhibited reduced lymph flow velocities and increased interstitial fluid pressure. Airways of LT?(-/-) mice infected with Mycoplasma pulmonis had significantly more lymphangiogenesis than wild type (WT) or LT?(-/-) mice, as did the skin draining immunization sites of LT?(-/-) mice. Macrophages, B cells, and T cells, known sources of LT and TNF?, were apparent in the skin surrounding the immunization sites as were LT?, LT?, and TNF? mRNAs. Ectopic expression of LT? led to the development of LYVE-1 and Prox1-positive lymphatic vessels within tertiary lymphoid organs (TLOs). Quantification of pancreatic lymphatic vessel density in RIPLT?LT?(-/-) and WT mice revealed that LT? was sufficient for inducing lymphangiogenesis and that LT? was not required for this process. Kidneys of inducible LT? transgenic mice developed lymphatic vessels before the appearance of obvious TLOs. These data indicate that LT? plays a significant role in lymphatic vessel function and in inflammation-associated lymphangiogenesis.

SUBMITTER: Mounzer RH

PROVIDER: S-EPMC2951858 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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Lymphotoxin-alpha contributes to lymphangiogenesis.

Mounzer Rawad H RH Svendsen Oyvind S OS Baluk Peter P Bergman Cheryl M CM Padera Timothy P TP Wiig Helge H Jain Rakesh K RK McDonald Donald M DM Ruddle Nancy H NH

Blood 20100621 12

Lymphotoxin-α (LTα), lymphotoxin-β (LTβ), and tumor necrosis factor-α (TNFα) are inflammatory mediators that play crucial roles in lymphoid organ development. We demonstrate here that LTα also contributes to the function of lymphatic vessels and to lymphangiogenesis during inflammation. LTα(-/-) mice exhibited reduced lymph flow velocities and increased interstitial fluid pressure. Airways of LTβ(-/-) mice infected with Mycoplasma pulmonis had significantly more lymphangiogenesis than wild type ...[more]

PMID: 20566898

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Project description:BackgroundIntervertebral disc degeneration (IVDD) is a primary cause of degenerative disc diseases; however, the mechanisms underlying the degeneration remain unclear. The immunoinflammatory response plays an important role in IVDD progression. The inflammatory cytokine lymphotoxin-α (LTα), formerly known as TNFβ, is associated with various pathological conditions, while its role in the pathogenesis of IVDD remains elusive.MethodsReal-time quantitative polymerase chain reaction (RT-qPCR), Western blotting (WB), and enzyme-linked immunosorbent assays were used to assess the levels of LTα in human nucleus pulposus (NP) tissues between degeneration and control groups. The plasma concentrations of LTα and C-reactive protein (CRP) were compared between healthy and IVDD patients. Rat primary NP cells were cultured and identified via immunofluorescence. Methyl-thiazolyl-tetrazolium assays and flow cytometry were used to evaluate the effects of LTα on rat NP cell viability. After NP cells were treated with LTα, degeneration-related molecules (Caspase-3, Caspase-1, matrix metalloproteinase (MMP) -3, aggrecan and type II collagen) were measured via RT-qPCR and WB.ResultsThe levels of both the mRNA and protein of LTα in human degenerated NP tissue significantly increased. Plasma LTα and CRP did not differ between healthy controls and IVDD patients. Rat primary NP cells were cultured, and the purity of primary NP cells was > 90%. Cell experiments showed inversely proportional relationships among the LTα dose, treatment time, and cell viability. The optimal conditions (dose and time) for LTα treatment to induce rat NP cell degeneration were 5 μg/ml and 48 ~ 72 h. The apoptosis rate and the levels of Caspase-3, Caspase-1, and MMP-3 significantly increased after LTα treatment, while the levels of type II collagen and aggrecan were decreased, and the protein expression levels were consistent with their mRNA expression levels.ConclusionsThis study demonstrated that elevated LTα is closely associated with IVDD and that LTα may induce NP cell apoptosis and reduce important extracellular matrix (ECM) proteins, which cause adverse effects on IVDD progress. Moreover, the optimal conditions for LTα treatment to induce NP cell degeneration were determined.

Project description:Organised meningeal immune cell infiltrates are suggested to play an important role in cortical grey matter pathology in the multiple sclerosis brain, but the mechanisms involved are as yet unresolved. Lymphotoxin-alpha plays a key role in lymphoid organ development and cellular cytotoxicity in the immune system and its expression is increased in the cerebrospinal fluid of naïve and progressive multiple sclerosis patients and post-mortem meningeal tissue. Here we show that persistently increased levels of lymphotoxin alpha in the cerebral meninges can give rise to lymphoid-like structures and underlying multiple sclerosis-like cortical pathology. Stereotaxic injections of recombinant lymphotoxin-alpha into the rat meninges led to acute meningeal inflammation and subpial demyelination that resolved after 28 days, with demyelination being dependent on prior sub-clinical immunisation with myelin oligodendrocyte glycoprotein. Injection of a lymphotoxin-alpha lentiviral vector into the cortical meningeal space, to produce chronic localised over-expression of the cytokine, induced extensive lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin+ fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid chemokines and their receptors. Extensive microglial and astroglial activation, subpial demyelination and marked neuronal loss occurred in the underlying cortical parenchyma. Whereas subpial demyelination was partially dependent on prior myelin oligodendrocyte glycoprotein immunisation, the neuronal loss was present irrespective of immunisation. Conditioned medium from LTα treated microglia was able to induce a reactive phenotype in astrocytes. Our results show that chronic lymphotoxin-alpha overexpression alone is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration, similar to that seen in the progressive multiple sclerosis brain.

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Lymphotoxin-alpha contributes to lymphangiogenesis.

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Lymphotoxin-alpha contributes to lymphangiogenesis.

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