Recently, Zhao Jiajun and Zhang Qunye of Shandong University published an article entitled "Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques" in the Journal of Experimental Medicine.
This study demonstrates that thyroid stimulating hormone (TSH), an independent risk factor for atherosclerosis, aggravates vascular inflammation and promotes the formation of atherosclerosis. Professor Zhao Jiajun from the Provincial Hospital affiliated to Shandong University and Professor Zhang Qunye from Qilu Hospital of Shandong University are co-authors.
Research Background
It has long been known that hypothyroidism is associated with hypercholesterolemia and cardiovascular disease and is attributed to a decrease in thyroid hormone levels. However, subclinical hypothyroidism (SH) patients also have an increased risk of hypercholesterolemia and cardiovascular disease, which is difficult to explain with the aforementioned theory. Because the thyroid hormone levels in these patients remain normal, only thyroid stimulating hormone levels are elevated. So, does thyroid-stimulating hormone play a role in atherosclerosis?
Thyroid stimulating hormone (TSH) is a glycoprotein hormone secreted by the pituitary gland, which is mainly used to stimulate the synthesis and secretion of thyroid hormone. However, TSH receptors are expressed not only in thyroid cells, but also in various cells such as hepatocytes, adipocytes, and osteoclasts, suggesting that its function is not limited to the regulation of thyroid function.
According to previous studies, TSH receptors are also expressed in macrophages, endothelial cells, and smooth muscle cells. These three types of cells are most closely related to atherosclerosis. Therefore, TSH may not only promote atherosclerosis indirectly by regulating the function of the thyroid, but also directly exert its effects through these cells. To test this hypothesis, the researchers analyzed the association between TSH and atherosclerosis.
TSH is positively associated with atherosclerosis
In this study, the researchers recruited 2,480 volunteers. After excluding the diseased subjects, they divided the remaining 1,103 subjects into three groups (normal thyroid function control, mild SH, and severe SH) based on TSH levels. Serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were significantly elevated in mild and severe patients compared to normal controls.
They found that carotid plaque incidence and carotid intima-media thickness (CIMT) were also significantly increased in groups with higher TSH levels. Furthermore, even after traditional cardiovascular factors (including age, dyslipidemia, and blood pressure) were controlled by multiple linear regression analysis, the positive correlation between TSH and CIMT was significant. Moreover, serum levels of several key inflammatory factors, including TNF-α, CCL-2, and IL-1β, were also significantly elevated. These results support the association between TSH and atherosclerosis.
Tshr knockdown attenuates atherosclerosis and vascular inflammation
To confirm the causal relationship between TSH and atherosclerosis, the researchers crossed Tshr +/− mice with ApoE −/− mice to obtain Tshr −/− ApoE −/− and Tshr +/+ ApoE −/ − mice. They fed a Western diet from 6 weeks of age until 12 or 16 weeks. Tshr −/− ApoE −/− mice maintain normal thyroid function through dietary thyroxine powder to rule out abnormalities in thyroid hormone levels.
The lipid parameters of the two groups of mice were comparable, but staining showed a significant reduction in plaque area in Tshr −/− ApoE −/− mice (Fig. 1). The F4/80 positive area in the mouse plaque was significantly reduced, indicating a decrease in the number of macrophages and a decrease in vascular inflammation, and decreased expression of F4/80, Il-1b, Il-6, Tnfa and Ccl2 in the aorta. . The immunohistochemical results of TNF-α and IL-6 also confirmed this. These results suggest that TSH promotes vascular inflammation and atherosclerosis through a mechanism that does not rely on thyroid hormones.
Figure 1. TSHR knockdown attenuates vascular inflammation and atherosclerosis.
TSH directly contributes to macrophage inflammatory response
Since macrophages play a key role in atherosclerosis, is this cell directly affected by TSH? First, the researchers confirmed the expression of TSHR in mouse peritoneal macrophages and plaque macrophages by immunofluorescence. Macrophages were then treated with TSH in vitro and induction of TNF-[alpha] and IL-6 was observed. In addition, TSH significantly up-regulated markers associated with acute inflammation (such as Nos2, Il6, and Tnfa) and down-regulated a range of markers associated with inflammatory regression (including Arg1, Pparg, Lxra, and Abca1). Therefore, TSH does contribute to the macrophage inflammatory response.
Notably, the two chemokines, Ccl2 and Cx3cl1, were also significantly induced during TSH treatment of macrophages, which are critical for the recruitment of monocytes in atherosclerosis. In addition to the recruitment of monocytes, the number of macrophages in plaques is also related to factors such as maturation, apoptosis and proliferation. The researchers found that TSH neither accelerated the maturation of monocytes, nor had a significant effect on F4/80 expression of monocytes or apoptosis of macrophages. Therefore, the knockdown of Tshr may not reduce the number of macrophages.
Myeloid-specific Tshr knockout delays atherosclerosis
To test whether the proinflammatory effects of TSH are associated with vascular inflammation and atherosclerosis in vivo, the researchers prepared ApoE by hybridizing Tshr flox / flox (provided by Safran Biotechnology) , LyzM-Cre + and ApoE −/− mice. −/− Background of myeloid-specific Tshr knockout mice (TSHR MKO mice). They found that the serum IL-6 and CCL2 levels were significantly reduced in the mice, indicating a reduction in systemic inflammation. In addition, staining results also showed a reduction in atherosclerosis in the TSHR MKO mice after 12 weeks and 16 weeks of Western diet. These results confirm that the effect of TSH on macrophages is pro-inflammatory and leads to atherosclerosis.
To reveal the underlying mechanisms of TSH pro-inflammatory effects, they further investigated a number of pathways associated with inflammation (Figure 2). They found that TSH stimulation resulted in p65 nuclear transport within 30 minutes, inducing IκB phosphorylation and IκBα degradation. In addition, TSH treatment also increased phosphorylation of ERK1/2, JNK, and p38α, suggesting that the MAPK pathway is also involved in the induction of related inflammation. TSHR alone is responsible for the activation of these pathways, as Tshr silencing significantly blocks these effects of TSH.
Figure 2. TSH promotes inflammation in macrophages via the IκB/NFκB and MAPK pathways.
"Based on studies in populations, knockout mice, and in vitro, we demonstrated that TSH can directly lead to atherosclerosis by promoting macrophage inflammation in plaques," the authors write.
The study reaffirmed how subclinical hypothyroidism increases cardiovascular risk and uses TSH as a potential target for the prevention and treatment of cardiovascular and other inflammatory diseases.
Original search
Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques
J Exp Med 2019 Apr 2. Epub 2019 Apr 2.
Http://dx.doi.org/10.1084/jem.20181473
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