Lymphotoxin β receptor signaling is required for inflammatory lymphangiogenesis in the thyroid

doi:10.1073/pnas.0606697104

Lymphotoxin β receptor signaling is required for inflammatory lymphangiogenesis in the thyroid

*Immunology Insitute and
Departments of ^†Pathology,
^‡Pharmacology and Biological Chemistry,
^§Otolaryngology, and
^¶Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029-6574

Edited by Nancy Ruddle, Yale University School of Medicine, New Haven, CT, and accepted by the Editorial Board January 22, 2007 (received for review August 3, 2006)

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 β receptor or lymphotoxin α 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 β receptor signaling in this process.

Footnotes

^‖To whom correspondence should be addressed at:
Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1630, New York, NY 10029-6574.
E-mail: sergio.lira{at}mssm.edu
Author contributions: G.C.F. and T.M. contributed equally to this work; G.C.F., T.M., E.G., M.S., and S.A.L. designed research; G.C.F., T.M., A.P.M., A.G., B.H., W.H., and M.S. performed research; G.C.F., T.M., A.P.M., A.G., B.K.C., and S.A.L. analyzed data; and G.C.F., T.M., M.S., and S.A.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission. N.R. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/cgi/content/full/0606697104/DC1.
Abbreviations:

HEV,

high endothelial venule;

LEC,

lymphatic endothelial cell;

LT,

lymphotoxin;

LTβR,

LTβ-receptor.