Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.

PloS One
Hiroaki J KimuraP Caturegli

Abstract

Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown. Using transgenic mice chronically expressing IFNgamma in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysis comparing transgenic to wild type thyrocytes revealed increased levels of immunoproteasome subunits like LMP2 in transgenics, suggesting an important role of the immunoproteasome in oncocyte pathogenesis. Pharmacologic blockade of the proteasome, in fact, ameliorated the oncocytic phenotype. Genetic deletion of LMP2 subunit prevented the development of the oncocytic phenotype and primary hypothyroidism. LMP2 was also found expressed in oncocytes from patients with Hashimoto thyroiditis and Hürthle cell tumors. In summary, we report that oncocytes are the result of an increased immunoproteasome expression secondary to a chronic inflammatory milieu, and suggest LMP2 as a novel therapeutic target for the treatment of oncocytic lesions and autoimmune hypothyroidism.

References

Aug 19, 1997·Proceedings of the National Academy of Sciences of the United States of America·M GroettrupP M Kloetzel
Jan 31, 1998·The Journal of Experimental Medicine·T A GriffinR A Colbert
Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·V J PalombellaM B Grisham
Nov 24, 1999·Molecular and Cellular Biology·T Hayashi, D Faustman
Mar 4, 2000·Proceedings of the National Academy of Sciences of the United States of America·P CaturegliN R Rose
Oct 4, 2000·Nature Medicine·B M KesslerH L Ploegh
Oct 4, 2000·Nature Medicine·H A RunnelsJ J Monaco
Oct 4, 2000·Nature Medicine·T HayashiD L Faustman
Jul 27, 2001·Diabetes Technology & Therapeutics·T Hayashi, D Faustman
Feb 21, 2002·The Oncologist·Julian Adams
May 1, 2002·Nature Biotechnology·Saurabh SahaVictor E Velculescu
Jul 10, 2003·Autoimmunity Reviews·Glinda S Cooper, Berrit C Stroehla
Feb 18, 2005·Journal of the American Society of Nephrology : JASN·Alejandro R ChadeLilach O Lerman
Mar 9, 2005·Thyroid : Official Journal of the American Thyroid Association·Patrizio Caturegli, Christine Ruggere
Apr 7, 2005·International Journal of Experimental Pathology·Hiroaki KimuraPatrizio Caturegli
Jul 9, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Alexander K NussbaumJ Lindsay Whitton
Jan 18, 2006·Annual Review of Medicine·Paul G RichardsonKenneth C Anderson
Apr 29, 2006·Arthritis and Rheumatism·Thomas EgererEugen Feist
Sep 8, 2007·Circulation Research·Joerg HerrmannAmir Lerman
Oct 31, 2007·Circulation Research·Tohru Fukai
Feb 16, 2008·Circulation Research·Antje Ludwig, Silke Meiners
May 21, 2008·Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme·S Benvenga
Aug 8, 2008·Archives of Pathology & Laboratory Medicine·Kathleen T MontoneVirginia A LiVolsi
Jan 16, 2009·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Keiji Tanaka
Jan 21, 2014·Pathology, Research and Practice·T Danielle SamulskiZubair Baloch

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Citations

Feb 9, 2011·Journal of Endocrinological Investigation·F GuaraldiP Caturegli
Dec 5, 2013·Endocrine-related Cancer·Lucas Leite CunhaLaura Sterian Ward
Jan 14, 2010·Thyroid : Official Journal of the American Thyroid Association·Patrizio Caturegli, Hiroaki Kimura
Nov 16, 2012·Thyroid : Official Journal of the American Thyroid Association·Patrizio CaturegliShintaro Iwama
Dec 5, 2015·Journal of Immunology Research·Hiroaki KimuraKoichi Suzuki
Oct 31, 2015·Scientific Reports·Hiroaki KimuraMasafumi Takahashi
Oct 19, 2017·Cancer Metastasis Reviews·Yulin ChenXing Guo
Oct 17, 2017·British Journal of Pharmacology·Michael BaslerMarcus Groettrup
Mar 4, 2021·Pathology International·Masanori Kasahara
May 21, 2021·Frontiers in Endocrinology·Sylvia L Asa, Ozgur Mete

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Datasets Mentioned

BETA
GSE15114

Methods Mentioned

BETA
transgenic
transgenics
genotyping
electron microscopy
dissection
electrophoresis

Software Mentioned

Stata

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