Dataset Information

Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid.

ABSTRACT: Infiltration of lymphocytes into the thyroid gland and formation of lymph node-like structures is a hallmark of Hashimoto's thyroiditis. Here we demonstrate that lymphatic vessels are present within these infiltrates. Mice overexpressing the chemokine CCL21 in the thyroid (TGCCL21 mice) developed similar lymphoid infiltrates and lymphatic vessels. TGCCL21 mice lacking mature T and B cells (RAGTGCCL21 mice) did not have cellular infiltrates or increased number of lymphatic vessels compared with controls. Transfer of CD3(+)CD4(+) T cells into RAGTGCCL21 mice promoted the development of LYVE-1(+)podoplanin(+)Prox-1(+) vessels in the thyroid. Genetic deletion of lymphotoxin beta receptor or lymphotoxin alpha abrogated development of lymphatic vessels in the inflamed areas in the thyroid but did not affect development of neighboring lymphatics. These results define a model for the study of inflammatory lymphangiogenesis in the thyroid and implicate lymphotoxin beta receptor signaling in this process.

SUBMITTER: Furtado GC

PROVIDER: S-EPMC1829258 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid.

Furtado Glaucia C GC Marinkovic Tatjana T Martin Andrea P AP Garin Alexandre A Hoch Benjamin B Hubner Wolfgang W Chen Benjamin K BK Genden Eric E Skobe Mihaela M Lira Sergio A SA

Proceedings of the National Academy of Sciences of the United States of America 20070314 12

Infiltration of lymphocytes into the thyroid gland and formation of lymph node-like structures is a hallmark of Hashimoto's thyroiditis. Here we demonstrate that lymphatic vessels are present within these infiltrates. Mice overexpressing the chemokine CCL21 in the thyroid (TGCCL21 mice) developed similar lymphoid infiltrates and lymphatic vessels. TGCCL21 mice lacking mature T and B cells (RAGTGCCL21 mice) did not have cellular infiltrates or increased number of lymphatic vessels compared with c ...[more]

PMID: 17360402

Similar Datasets

Project description:BACKGROUND:Lymphotoxin β receptor (LTβR) plays important roles in the development of the immune system and immune response. At the cellular level, ligand-bound LTβR activates the pro-inflammatory NF-κB pathway but the detailed mechanisms regulating its signaling remain unknown. Understanding them is of high importance since LTβR and its ligands are promising therapeutic targets. Here, we studied the consequences of perturbed cellular cholesterol content on LTβR-induced NF-κB signaling. METHODS:To modulate cholesterol availability and/or level in lung carcinoma A549 and H2228, and endothelial HUVEC cells different treatment regimens with filipin, methyl-β-cyclodextrin and simvastatin were applied. LTβR localization was studied by confocal microscopy. The activity of LTβR-induced NF-κB pathway was assessed by measuring the levels of NF-κB pathway inhibitor IκBα and phosphorylation of RelA transcription factor by Western blotting. The NF-κB transcriptional response, production of chemokines and adhesion molecules were examined by qRT-PCR, ELISA, and Western blotting, respectively. Adherence of different types of primary immune cells to epithelial A549 cells and endothelial HUVECs was measured fluorometrically. Interactions of LTβR with its protein partners were investigated by immunoprecipitation. RESULTS:We showed that filipin-mediated sequestration of cholesterol or its depletion from the plasma membrane with methyl-β-cyclodextrin impaired LTβR internalization and potentiated LTβR-dependent activation of the canonical branch of the NF-κB pathway. The latter was manifested by enhanced degradation of IκBα inhibitor, elevated RelA phosphorylation, substantial increase in the expression of NF-κB target genes encoding, among others, cytokines and adhesion molecules known to play important roles in immune response. It was followed by robust secretion of CXCL8 and upregulation of ICAM1, that favored the adhesion of immune cells (NK and T cells, neutrophils) to A549 cells and HUVECs. Mechanistically, we showed that cholesterol depletion stabilized interactions of ligand-stimulated LTβR with modified forms of TRAF2 and NEMO proteins. CONCLUSIONS:Our results showed that the reduction of the plasma membrane content of cholesterol or its sequestration strongly potentiated signaling outcome initiated by LTβR. Thus, drugs modulating cholesterol levels could potentially improve efficacy of LTβR-based therapies. Video abstract.

Dataset Information

Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid.

Publications

Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets