TY - JOUR
T1 - CD5L Constitutes a Novel Biomarker for Integrated Hepatic Thyroid Hormone Action
AU - Nock, Sebastian
AU - Johann, Kornelia
AU - Harder, Lisbeth
AU - Wirth, Eva Katrin
AU - Renko, Kostja
AU - Hoefig, Carolin S.
AU - Kracke, Vanessa
AU - Hackler, Julian
AU - Engelmann, Beatrice
AU - Rauner, Martina
AU - Köhrle, Josef
AU - Schomburg, Lutz
AU - Homuth, Georg
AU - Völker, Uwe
AU - Brabant, Georg
AU - Mittag, Jens
N1 - Funding Information:
This work was generously supported by the German Research Foundation DFG as part of the priority program ‘‘SPP 1629—Thyroid Trans Act’’ (grant numbers Mi1242/5-1, Mi1242/4-1, HO5096/2-1, RA1923/6-1, and BR915/12-1) to J.M., C.S.H., M.R., and G.B., the Heisenberg Program Mi1242/2-2 to J.M., the GRK1957 ‘‘Adipocyte-Brain-Crosstalk,’’ and Research Unit FOR-2558 ‘‘TraceAge’’ (Scho 849/6-1) to J.H. and L.S.
Publisher Copyright:
© 2020, Mary Ann Liebert, Inc., publishers.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Background: Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed by using serum concentrations of thyrotropin (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. Methods: Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in-depth characterization of the underlying cellular mechanisms, primary mouse cells were used. Results: The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared with euthyroid controls across the two species. These originated predominantly from liver, spleen, and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from proinflammatory M1 macrophages, which are similar to liver-residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ-dependent hepatocyte-derived signaling, the in vivo regulation of Cd5l expression depended on both TR isoforms. Conclusion: Our results identify several novel targets of TH action in serum, with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.
AB - Background: Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed by using serum concentrations of thyrotropin (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. Methods: Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in-depth characterization of the underlying cellular mechanisms, primary mouse cells were used. Results: The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared with euthyroid controls across the two species. These originated predominantly from liver, spleen, and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from proinflammatory M1 macrophages, which are similar to liver-residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ-dependent hepatocyte-derived signaling, the in vivo regulation of Cd5l expression depended on both TR isoforms. Conclusion: Our results identify several novel targets of TH action in serum, with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.
UR - http://www.scopus.com/inward/record.url?scp=85086346336&partnerID=8YFLogxK
U2 - 10.1089/thy.2019.0635
DO - 10.1089/thy.2019.0635
M3 - Journal articles
C2 - 32183611
AN - SCOPUS:85086346336
VL - 30
SP - 908
EP - 923
JO - Thyroid
JF - Thyroid
SN - 1050-7256
IS - 6
ER -