title: Disruption of the TSLP-TSLPR-LAP signaling between epithelial and dendritic cells through hyperlipidemia contributes to regulatory T-Cell defects in atherosclerotic mice.
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.
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kunwu
authors.initials: K
authors.lastname: Yu
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Mao
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Meng
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Bangwei
authors.initials: B
authors.lastname: Wu
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hasahya
authors.initials: H
authors.lastname: Tony
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Huairui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China. Electronic address: bushyukunwu@126.com.
authors.forename: Qiutang
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000008:administration & dosage / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006949:Hyperlipidemias / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007108:Immune Tolerance; D007136:Immunoglobulins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000302:isolation & purification / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007136:Immunoglobulins; D008077:Lipoproteins, LDL; D010455:Peptides; D018121:Receptors, Cytokine; C410591:Tslpr protein, mouse; C099252:oxidized low density lipoprotein; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse
keywords: Atherosclerosis; Dendritic cell; Low-density lipoprotein (LDL); Regulatory T-cell (Treg); Thymic stromal lymphopoietin (TSLP)