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

Atherosclerosis. 2015 Feb;238(2):278-88. doi: 10.1016/j.atherosclerosis.2014.12.019. Epub 2014 Dec 18.

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.

Keywords: Atherosclerosis; Dendritic cell; Low-density lipoprotein (LDL); Regulatory T-cell (Treg); Thymic stromal lymphopoietin (TSLP).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics
  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Cell Communication* / drug effects
  • Cell Differentiation
  • Cells, Cultured
  • Coculture Techniques
  • Cytokines / administration & dosage
  • Cytokines / metabolism*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism*
  • Forkhead Transcription Factors / metabolism
  • Hyperlipidemias / genetics
  • Hyperlipidemias / immunology
  • Hyperlipidemias / metabolism*
  • Hyperlipidemias / pathology
  • Immune Tolerance
  • Immunoglobulins / metabolism*
  • Lipoproteins, LDL / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptides / isolation & purification
  • Peptides / metabolism*
  • Receptors, Cytokine / agonists
  • Receptors, Cytokine / metabolism*
  • Signal Transduction* / drug effects
  • Spleen / immunology
  • Spleen / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • Thymic Stromal Lymphopoietin
  • Thymus Gland / immunology
  • Thymus Gland / metabolism

Substances

  • Apolipoproteins E
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Immunoglobulins
  • Lipoproteins, LDL
  • Peptides
  • Receptors, Cytokine
  • Tslpr protein, mouse
  • oxidized low density lipoprotein
  • Thymic Stromal Lymphopoietin
  • TSLP protein, mouse