Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells.
Hypothyroidism in humans is characterized by severe neurological consequences that are often irreversible, highlighting the critical role of thyroid hormone (TH) in the brain. Despite this, not much is known about the signaling pathways that control TH action in the brain. What is known is that the prohormone thyroxine (T4) is converted to the active hormone triiodothyronine (T3) by type 2 deiodinase (D2) and that this occurs in astrocytes, while TH receptors and type 3 deiodinase (D3), which inactivates T3, are found in adjacent neurons. Here, we modeled TH action in the brain using an in vitro coculture system of D2-expressing H4 human glioma cells and D3-expressing SK-N-AS human neuroblastoma cells. We found that glial cell D2 activity resulted in increased T3 production, which acted in a paracrine fashion to induce T3-responsive genes, including ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), in the cocultured neurons. D3 activity in the neurons modulated these effects. Furthermore, this paracrine pathway was regulated by signals such as hypoxia, hedgehog signaling, and LPS-induced inflammation, as evidenced both in the in vitro coculture system and in in vivo rat models of brain ischemia and mouse models of inflammation. This study therefore presents what we believe to be the first direct evidence for a paracrine loop linking glial D2 activity to TH receptors in neurons, thereby identifying deiodinases as potential control points for the regulation of TH signaling in the brain during health and disease.
Freitas
Beatriz C G
BC
Laboratory of Molecular Endocrinology, Division of Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo SP, Brazil.
Gereben
Balázs
B
Castillo
Melany
M
Kalló
Imre
I
Zeöld
Anikó
A
Egri
Péter
P
Liposits
Zsolt
Z
Zavacki
Ann Marie
AM
Maciel
Rui M B
RM
Jo
Sungro
S
Singru
Praful
P
Sanchez
Edith
E
Lechan
Ronald M
RM
Bianco
Antonio C
AC
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002477:Cells / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D012377:Rodentia / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013974:Thyroxine / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000235:genetics / Q000378:metabolism*
D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine; D007453:Iodide Peroxidase; D013974:Thyroxine
Nature. 2003 Nov 13;426(6963):178-81
14614506
J Clin Invest. 2003 Jul;112(2):189-96
12865408
Nat Neurosci. 2003 Jan;6(1):21-7
12469128
Endocrinology. 1997 Aug;138(8):3359-68
9231788
Endocrinology. 2007 Oct;148(10):4786-92
17628010
Endocrinology. 2004 Apr;145(4):1649-55
14684601
Am J Hum Genet. 2004 Jan;74(1):168-75
14661163
Glia. 2000 Apr;30(2):105-21
10719353
Prog Brain Res. 2006;153:189-207
16876576
Toxicology. 2002 Dec 27;181-182:179-82
12505306
Thyroid. 2003 Nov;13(11):1005-12
14651784
Front Neuroendocrinol. 2007 Aug-Sep;28(2-3):97-114
17588648
Nat Cell Biol. 2005 Jul;7(7):698-705
15965468
Endocrinology. 1999 Nov;140(11):5443-6
10537178
J Clin Invest. 2008 Mar;118(3):975-83
18259611
Development. 1999 Jul;126(13):2901-9
10357934
Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10391-6
9294221
Nature. 2006 Jan 26;439(7075):484-9
16400329
Endocrinology. 2007 Oct;148(10):4865-74
17628004
Endocr Rev. 1997 Aug;18(4):462-75
9267760
Stroke. 2009 Nov;40(11):3618-26
19762700
J Endocrinol. 2004 Aug;182(2):315-23
15283692
Cell Signal. 2009 Sep;21(9):1351-5
19249355
Endocrinology. 2006 Apr;147(4):1735-43
16396983
Stroke. 1989 Jan;20(1):84-91
2643202
Front Neuroendocrinol. 2010 Apr;31(2):134-56
20074584
Neurobiology (Bp). 1998;6(2):141-50
9785350
J Neurosci. 1999 Oct 15;19(20):8954-65
10516314
Endocrinology. 2009 Jan;150(1):540-5
18787028
Nat Clin Pract Endocrinol Metab. 2007 Mar;3(3):249-59
17315033
J Neuroendocrinol. 2008 Jun;20(6):784-94
18601701
Endocrinology. 1988 May;122(5):1860-8
3359966
Endocrinology. 2002 Oct;143(10):3846-53
12239096
Endocrinology. 1999 Feb;140(2):784-90
9927306
Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14466-71
17720805
J Clin Invest. 2005 Sep;115(9):2524-33
16127464
Mol Endocrinol. 2001 Dec;15(12):2137-48
11731615
Endocrinology. 2009 Apr;150(4):1976-83
19036883
J Neurosci. 2009 Aug 19;29(33):10299-308
19692604
Diabetes. 2007 Mar;56(3):767-76
17327447
Glia. 2005 Feb;49(3):430-44
15546152
J Clin Endocrinol Metab. 2003 Jun;88(6):2825-30
12788895
Mol Cell Neurosci. 2005 Jul;29(3):414-26
15950154
J Neuroendocrinol. 2001 Sep;13(9):741-8
11578523
Lancet. 2004 Oct 16-22;364(9443):1435-7
15488219
Endocrinology. 2007 Jul;148(7):3080-8
17332058
Endocrinology. 2005 Dec;146(12):5128-34
16150911
J Biol Chem. 2000 Jul 7;275(27):20861-6
10877845
Brain Res. 2004 Sep 3;1019(1-2):210-6
15306255
Endocrinology. 1982 Feb;110(2):367-75
6276132
Endocrinology. 2001 Dec;142(12):5190-7
11713214
Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):223-36
17574005
Endocrinology. 1998 Jun;139(6):2879-84
9607797