Thymic Stromal Lymphopoietin Over-Expressed in Human Atherosclerosis: Potential Role in Th17 Differentiation

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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.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Thymic stromal lymphopoietin (TSLP) mediates inflammation and is essential for allergic inflammation. In a preliminary study, we showed that TSLP plays an important role in the innate and adaptive immune system and is over-expressed in human atherosclerotic plaques [8,9]. …”

Section: Introductionmentioning

confidence: 99%

“…It mediates various types of allergic inflammation, such as atopic dermatitis and asthma, and plays an important role in the polarisation of dendritic cells (DCs) to drive T helper (Th) 2 cytokine production [11,12,15,16,17]. Ox-LDL can induce TSLP expression in human vascular smooth muscle cells (HVSMCs) and human umbilical vein endothelial cells (HUVECs), and angiotensin II can induce primary vascular smooth muscle cells (VSMCs) to express TSLP [8,9]. In addition, TSLP can promote the Th17 immune response in vitro , which may be implicated in Th17 inflammation in atherosclerosis through DC activation; Angiotensin II-induced TSLP enhances the Th17-driven immune response in atherosclerosis and hypertension [8,9].…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Peng²,

Dong³

et al. 2013

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Background: Thymic stromal lymphopoietin (TSLP) has been shown to be expressed in various inflammatory tissues, such as human atherosclerotic plaques. Many types of myeloid cells involved in atherosclerosis, including mast cells, lymphocytes, dendritic cells and monocytes/macrophages, present TSLP receptors (TSLPR). However, it is unknown whether platelets, which also play important roles in atherothrombosis, express TSLPR. Methods and Results: We applied flow cytometry and western blotting to show that TSLPR was expressed on the surface of human platelets. Following the addition of TSLP to platelets, the expression of CD62P, CD63, PAC-1 and p-Akt as well as aggregation and ATP release were increased significantly. A TSLPR antibody and a PI3K (phosphatidylinositol 3-kinase) enzyme inhibitor (LY294002) significantly inhibited the platelet activation induced by TSLP. The expression of TSLPR, CD62P and CD63 and the increment of the expression of CD62P and CD63 induced by TSLP in the acute coronary syndrome (ACS) group were markedly higher than those in the control group and the stable angina pectoris (SAP) group. The expression and the increment of the expression of CD62P and CD63 induced by TSLP were positively correlated with the expression of TSLPR. Conclusion: Human platelets express functional TSLPR, which can be activated by TSLP to promote platelet activation. TSLP/TSLPR functions via activating the PI3K/AKT pathway, and this signalling pathway may be one of the mechanisms involved in thrombosis in ACS. In coronary disease patients, the determination of TSLPR in platelets may help to identify the risk of ACS.

“…SGK1 has been most recently shown to participate in the signaling inducing pathogenic Th17 cells which drive autoimmune disease [11,12]. DCs and NF-κB signaling both participate in the regulation of Th17 cells [13,14]. The role of SGK1 in DCs has, however not been investigated yet.…”

Section: Introductionmentioning

confidence: 99%

Serum- and Glucocorticoid-Inducible Kinase 1 Sensitive NF-κB Signaling in Dendritic Cells

Schmid

Xuân

Zahir

et al. 2014

Background/Aims: Dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity, are required for initiation of specific T cell-driven immune responses. Phosphoinositide-3-kinase (PI3K) suppresses proinflammatory cytokine production in DCs, which limits T helper (Th1) polarization. PI3K is in part effective by downregulation of transcription factor NF-κB. Downstream signaling elements of PI3K include serum- and glucocorticoid-inducible kinase 1 (SGK1) and its phosphorylation target N-myc downstream regulated gene 1 (NDRG1). The present study explored whether SGK1 and NDRG1 play a role in the regulation of NF-κB and DC-maturation. Methods: DCs were isolated from bone marrow (BMDCs) or spleen of mice lacking functional SGK1 (sgk1^-/-) and corresponding wild type mice (sgk1^+/+). Protein abundance was determined by Western blotting. Transcription was inhibited by siRNA. Abundance of maturation markers was quantified by flow cytometry. FITC-dextran uptake was determined to quantify phagocytosis. Results: NDRG1 was similarly expressed in sgk1^+/+ and sgk1^-/-BMDCs, but SGK1-dependent phosphorylation of NDRG-1 was decreased in sgk1^-/-BMDCs. Silencing of NDRG1 in sgk1^+/+BMDCs as compared to control empty vector-treated BMDCs enhanced nuclear abundance of NF-κB subunit p65. Moreover, the abundance of phosphorylated NF-κB inhibitor IκBa, of phosphorylated IκB kinase (IKKa/ß) and of nuclear p65 were significantly higher in sgk1^-/-BMDCs than in sgk1^+/+BMDCs. Expression of maturation markers, MHC II, and CD86, was significantly larger and phagocytic capacity was significantly lower in sgk1^-/- than in sgk1^+/+BMDCs. Expression of CD86 and MHCII was also significantly higher in DCs isolated from the spleen of sgk1^-/- mice than those from sgk1^+/+mice. Conclusion: SGK1 and NDRG1 participate in the regulation of NF-κB signaling in and maturation of DCs.