Human Platelets Express Functional Thymic Stromal Lymphopoietin Receptors: a Potential Role in Platelet Activation in Acute Coronary Syndrome

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Aims: Thymic stromal lymphopoietin (TSLP) plays an important role in inflammatory diseases and is over-expressed in human atherosclerotic artery specimens. The present study investigated the role of TSLP in platelet activation and thrombosis models in vitro and in vivo, as well as the underlying mechanism and signaling pathway. Methods and Results: Western blotting and flow cytometry demonstrated that the TSLP receptor was expressed on murine platelets. According to flow cytometry, platelet stimulation with TSLP induced platelet degranulation and integrin αIIbβ3 activation. A TSLPR deficiency caused defective platelet aggregation, defective platelet secretion and markedly blunted thrombus growth in perfusion chambers at both low and high shear rates. TSLPR KO mice exhibited defective carotid artery thrombus formation after exposure to FeCl₃. TSLP increased Akt phosphorylation, an effect that was abrogated by the PI3K inhibitors wortmannin and LY294002. The PI3K inhibitors further diminished TSLP-induced platelet activation. TSLP-mediated platelet degranulation, integrin αIIbβ3 activation and Akt phosphorylation were blunted in platelets that lacked the TSLP receptor. Conclusion: This study demonstrated that the functional TSLPR was surface-expressed on murine platelets. The inflammatory cytokine TSLP triggered platelet activation and thrombus formation via TSLP-dependent PI3K/Akt signaling, which suggests an important role for TSLP in linking vascular inflammation and thrombo-occlusive diseases.

“…Our previous study demonstrated that the TSLPR was expressed on human platelets [34]. Our data demonstrated that the TSLPR was expressed on murine platelets (Fig.…”

Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 93%

Inflammatory Cytokine TSLP Stimulates Platelet Secretion and Potentiates Platelet Aggregation via a TSLPR-Dependent PI3K/Akt Signaling Pathway

Dong

Lin

Wang

et al. 2015

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“…Immunoblotting was performed as previously described [13,19,20]. Lysates from macrophages were prepared as previously described.…”

Section: Immunoblottingmentioning

confidence: 99%

Dopamine D1-Like Receptors Suppress the Proliferation of Macrophages Induced by Ox-LDL

Yao

Yang

Han

et al. 2016

Background/Aims: Oxidized low-density lipoprotein (Ox-LDL) induces macrophage proliferation, a key physiological process which leads to atherosclerosis. The aim of this study was to determine the effects of dopamine D₁-like receptors on macrophage proliferation induced by Ox-LDL. Methods: The expression of dopamine D₁-like receptors was determined by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting. The effect of D₁-like receptors on macrophage proliferation induced by Ox-LDL was measured by ³[H]-thymidine incorporation and cell number count. Results: Dopamine D₁-like receptors were present in macrophages as determined by immunohistochemistry, RT-PCR and immunoblotting. A D₁-like receptor agonist, fenoldopam, which by itself had no effect on macrophage proliferation, inhibited the stimulatory effect of Ox-LDL on macrophage proliferation. This was further confirmed by the D₁-like receptor antagonist SCH 23390 blocking the effect of fenoldopam, thereby indicating that the fenoldopam action was receptor specific. Phosphatidylinositol 3-kinase (PI3K/Akt) and mitogen-activated protein kinase (MAPK/ERK) pathways were also involved in the proliferative effect of Ox-LDL because in the presence of PI3K/Akt or MAPK/ERK inhibitors, LY294002 or PD98059, the stimulatory effects of Ox-LDL were blocked. Moreover, the stimulatory effect of Ox-LDL on the phosphorylation of ERK and Akt was significantly reduced by fenoldopam in macrophages. Additional experiments found that both D₁ and D₅ receptor expression was lower in the peritoneal macrophages from Apolipoprotein E-deficient mice compared to the control C57Bl/6J mice. Conclusions: Macrophages express D₁-like receptors. The activation of the D₁-like receptors significantly inhibits Ox-LDL-induced macrophage proliferation, possibly through the inhibition of the PI3K/Akt and MAPK/ERK signaling pathways.

“…The activation of inflammation, which involves several types of immune cells and their effector chemokines and cytokines, leads to plaque destabilization and disruption as well as thrombus formation and eventually results in ACS [32][33][34]. As a critical player in innate and adaptive immune response, DCs have important roles in immune processes involved in atherosclerosis and in the initiation of ACS [17,34,35].…”

Section: Discussionmentioning

confidence: 99%

IFN Regulatory Factor-1 Modulates the Function of Dendritic Cells in Patients with Acute Coronary Syndrome

Guo

Yan

Wang

et al. 2015

Background: Atherosclerosis is widely recognized as a complex inflammatory disease involving pathogenic immune response of T cells and antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages. Accumulating evidence has revealed that mature DCs play critical roles in the differentiation of effector T cells into CD4+ T cells, which effectively participate in the onset of acute coronary syndrome (ACS). IFN regulatory factor (IRF)-1 has been shown to be involved in various immune processes. The role of IRF-1 in DCs in the pathogenesis of ACS has not been investigated. Methods and Results: We examined the relative mRNA and protein expression of IRF-1 in human monocyte-derived DCs in patients with coronary artery disease (CAD). The overexpression or silencing of IRF-1 expression in DCs in patients with ACS was performed to explore the possible role of IRF-1 in the maturation and function of DCs involved in ACS. The results showed that the relative expression of IRF-1 in DCs is obviously increased in patients with ACS. The overexpression or silencing of IRF-1 expression could effectively promote or attenuate the maturation and function of DCs. In addition, we revealed that the MAPK pathway (phosphorylation of JNK, p38 and ERK1/2) might be downstream of IRF-1 signalling pathway in activation of circulating DCs in ACS patients. Conclusion: The present data demonstrate that IRF-1 could effectively promote the immune maturation and function of DCs in ACS patients.