CD5L Constitutes a Novel Biomarker for Integrated Hepatic Thyroid Hormone Action

Abstract

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 TRa1 in immune cells and the TRbdependent 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.

Profiling the serum proteome during Schistosoma mansoni infection in the BALB/c mice: A focus on the altered lipid metabolism as a key modulator of host-parasite interactions

“…In our findings, CD5 antigen-like (Q9QWK4) exhibited increased abundance in both investigated time points. As a classically described immune effector, its expression is positively regulated under inflammatory circumstances ( 21 ), justifying its interpretation as a potential biomarker of liver damage ( 21 , 26 , 27 ). To our knowledge, we are the first to report on the differential abundance of CD5 antigen like in the sera of S. mansoni infected animals.…”

The Nutritional Supply of Iodine and Selenium Affects Thyroid Hormone Axis Related Endpoints in Mice

“…TH exert their effect via interaction with nuclear THR, which regulate the expression of numerous target genes. It is estimated that 3% to 13% of hepatic genes are regulated by T3 [58,59]. These include Dio1, Thrsp [60,61], important in the regulation of lipid metabolism, but also Me1 [62,63], generating NADPH for fatty acid biosynthesis.…”

We All Know We Need Them, We Hope They Are Coming, But When?

“…Subsequent studies will also determine whether these markers exhibit sufficient sensitivity to detect subtle changes in thyroid status and specificity to be used clinically. Nonetheless, the data presented by Knock et al (5) are exciting and should encourage further research in this important field. That TH signaling exhibits such a high degree of tissue specificity is remarkable.…”

“…How can we assess TH actions in individual tissues? In the current issue of Thyroid, Knock et al (5) described how they utilized untargeted proteomics analyses of human and mouse plasma to identify 16 proteins produced in liver, spleen, or bone that respond to TH and might function as novel biomarkers of TH action.…”