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      Disruption of the TSLP-TSLPR-LAP signaling between epithelial and dendritic cells through hyperlipidemia contributes to regulatory T-Cell defects in atherosclerotic mice.

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          Abstract

          Regulatory T-Cells (Tregs) play a protective role against the development of atherosclerosis. Moreover, thymic stromal lymphopoietin (TSLP)/thymic stromal lymphopoietin receptor (TSLPR) signaling in myeloid dendritic cells (DCs) promote Treg differentiation. Here, we examined the potential role of TSLP/TSLPR on Treg homeostasis in atherosclerosis. The frequencies of both latency-associated peptide (LAP)(+) and Foxp3(+) Tregs were reduced in the thymus and spleen of ApoE(-/-) mice compared with C57BL/6 mice, and this effect was associated with decreased thymic output. The tolerogenic function of DCs obtained from ApoE(-/-) mice was compromised compared with those from C57BL/6 mice. The expression of TSLP and TSLPR was also inhibited in ApoE(-/-) mice. In addition, we found that ox-LDL attenuated TSLP expression in cultured thymic epithelial cells (TECs) through the activation of retinoid X receptor alpha (RXRA) and IL-1β and decreased LAP and PD-L1 expression in oxLDL-activated DCs while both were up-regulated in TSLP-activated DCs. We also observed that the TSLP-DCs mediated differentiation of Tregs was abrogated through LAP neutralization. Furthermore, TSLP injection rescued Treg defects in ApoE(-/-) mice. These findings suggest that Treg defects in ApoE(-/-) mice might partially be attributed to the disruption of TSLP-TSLPR-LAP signaling in epithelial cells (ECs) and DCs.

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          Author and article information

          Journal
          Atherosclerosis
          Atherosclerosis
          1879-1484
          0021-9150
          Feb 2015
          : 238
          : 2
          Affiliations
          [1 ] Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
          [2 ] Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China; Department of Cardiology, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
          [3 ] Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China.
          [4 ] Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China. Electronic address: bushyukunwu@126.com.
          Article
          S0021-9150(14)01639-6
          10.1016/j.atherosclerosis.2014.12.019
          25544178
          38e4d105-ae7b-4f3b-9097-e836f0f4cbc4
          Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
          History

          Atherosclerosis,Dendritic cell,Low-density lipoprotein (LDL),Regulatory T-cell (Treg),Thymic stromal lymphopoietin (TSLP)

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