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CYP51-mediated cholesterol biosynthesis is required for the proliferation of CD4+ T cells in Sjogren’s syndrome

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Abstract

CYtochrome P450, family 51 (CYP51) is an important enzyme for de novo cholesterol synthesis in mammalian cells. In the present study, we found that the expression of CYP51 positively correlated with CD4+ T cell activation both in vivo and in vitro. The addition of ketoconazole, a pharmacological inhibitor of CYP51, prevented the proliferation and activation of anti-CD3/CD28-expanded mouse CD4+ T cells in a dose-dependent fashion. Liquid chromatography-tandem mass spectrometry indicated an increase in levels of lanosterol in T cells treated with ketoconazole during activation. Ketoconazole-induced blockade of the cholesterol synthesis pathway also caused Sterol regulatory element binding protein 2 (SREBP2) activation in CD4+ T cells. Additionally, ketoconazole treatment elicited an integrated stress response in T cells that up-regulated activating transcription factor 4 (ATF4) and DNA-damage inducible transcript 3 (DDIT3/CHOP) at the translational level. Furthermore, treatment with ketoconazole significantly decreased the amount of CD4+ T cells infiltrating lesions in the submandibular glands of NOD/Ltj mice. In summary, our results suggest that CYP51 plays an essential role in the proliferation and survival of CD4+ T cells, which makes ketoconazole an inhibitor of CD4+ T cell proliferation and of the SS-like autoimmune response through regulating the biosynthesis of cholesterol and inducing the integrated stress response.

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Availability of data and materials

Data banks/repositories corresponding to all datasets analyzed in this study were listed in Additional file 1.

Abbreviations

ABCA1:

ATP-binding cassette transporter A 1

ABCG1:

ATP-binding cassette transporter G 1

ATF4:

Activating transcription factor 4

BIM:

Bcl-2 interacting mediator of cell death

BP:

Biological process

CDK2:

Cyclin-dependent kinase 2

CDK4:

Cyclin-dependent kinase 4

CFSE:

5-(And -6) -Carboxyfluorescein Daicetate Succinimidyl Ester

CYP51:

Lanosterol 14alpha-demethylase

Cyp51:

Cytochrome P450 family 51

CYP51A1:

Cytochrome P450 family 51 subfamily A member 1

Ddit3:

DNA-damage inducible transcript 3

DEGs:

Differentially expressed genes

DMSO:

Dimethyl sulfoxide

Eif2ak3:

Eukaryotic translation initiation factor 2 alpha kinase 3

FDPS:

Farnesyl pyrophosphate synthase

FBS:

Fetal bovine serum

GEO:

Gene Expression Omnibus database

GO:

Gene Ontology

GSEA:

Gene Set Enrichment Analysis

H&E:

Hematoxylin & eosin

HMGCR:

Hydroxymethylglutaryl-CoA reductase

HMG-CoA:

3-Hydroxy-3-methyl glutaryl coenzyme A reductase

IFN-γ:

Interferon-γ

IL-17:

Interleukin-17

IL-2:

Interleukin-2

HMGCR:

Hydroxymethylglutaryl-CoA reductase

IDI1:

Isopentenyl pyrophosphate isomerase 1

IL-6:

Interleukin-6

JNK/STAT:

Janus kinase/signal transducer and activator of transcription

KTC:

Ketoconazole

LC–MS:

Liquid chromatography-tandem mass spectrometry

ISR:

Integrated stress response

LXRβ:

Liver x receptor β

MBCD:

Methyl-β-cyclodextrin

MCL-1:

Myeloid cell leukemia-1

mRNA:

Messenger RNAs

NCBI:

National Center for Biotechnology Information

p38MAPK:

P38 mitogen-activated protein kinase

PBS:

Phosphate buffered saline

PCR:

Polymerase chain reaction

PBMC:

Peripheral blood mononuclear cell

PERK:

Protein kinase RNA–like endoplasmic reticulum kinase

RA:

Rheumatoid arthritis

SEM:

Standard deviations of the mean

SFR:

Salivary flow rate

siRNA:

Small-hairpin RNA

SLE:

Systematic lupus erythematosus

SQLE:

Squalene epoxidase

SREBP2:

Sterol regulatory element binding protein2

SS:

Sjogren’s syndrome

Th1:

T helper 1

TNF-α:

Tumor necrosis factor-α

7-DHC:

7-Dehydrocholesterol

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Acknowledgments

The flow cytometry and confocal analysis were performed in Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine. We are grateful for the contributions of their professional assistant. We would like to express our gratitude to EditSprings (https://www.editsprings.cn/) for the expert linguistic services provided.

Funding

This research was funded by the National Natural Science Foundation of China (Grants No. 82001064, 82201086, 82170976, 81970951); Yangfan program of Shanghai Science and Technology Committee (22YF1422100); Fundamental research program funding of Ninth People’s Hospital affiliated to Shanghai Jiao Tong university School of Medicine (JYZZ132); Biological sample bank project of Ninth People’s Hospital Affiliated to Shanghai Jiao Tong university School of Medicine (YBKB202107); The Cross project of Shanghai Ninth people’s hospital affiliated to Shanghai Jiaotong University of Medicine and Shanghai Science and Technology University (JYJC202126); The 15th undergraduate training program for innovation of Shanghai Jiaotong University School of medicine (1521Y591); and the Shanghai Summit & Plateau Disciplines.

Author information

Author notes

  1. Junhao Yin and Jiayao Fu have contributed equally to this work.

Authors and Affiliations

  1. Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China

    Junhao Yin, Jiayao Fu, Yanxiong Shao, Jiabao Xu, Hui Li, Changyu Chen, Chuangqi Yu, Lingyan Zheng & Baoli Wang

  2. National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China

    Junhao Yin, Jiayao Fu, Yanxiong Shao, Jiabao Xu, Hui Li, Changyu Chen, Chuangqi Yu, Lingyan Zheng & Baoli Wang

  3. Shanghai Key Laboratory of Stomatology, Shanghai, China

    Junhao Yin, Jiayao Fu, Yanxiong Shao, Jiabao Xu, Hui Li, Changyu Chen, Chuangqi Yu, Lingyan Zheng & Baoli Wang

  4. Department of Oral and Maxillofacial Surgery, Shanghai Stomatological Hospital, Fudan University, 1258 Fuxin Zhong Road, Shanghai, China

    Yijie Zhao

  5. Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

    Zhanglong Zheng

Authors
  1. Junhao Yin
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  2. Jiayao Fu
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  3. Yanxiong Shao
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  4. Jiabao Xu
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  5. Hui Li
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  6. Changyu Chen
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  7. Yijie Zhao
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  8. Zhanglong Zheng
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  9. Chuangqi Yu
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  10. Lingyan Zheng
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  11. Baoli Wang
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Contributions

Junhao Yin has a substantial contribution to the conception and design of this study, acquisition of experimental data, analysis of data, formal analysis and draft of the article. Jiayao Fu contributes to interpretation of data and paper writing. Yanxiong Shao contributes to methology. Jiabao Xu contributes to experimental validation and data curation. Hui Li contributes to experimental validation. Changyu Chen contributes to paper writing. Yijie Zhao and Zhanglong Zheng contribute to analysis of data. Chuangqi Yu has a substantial to design of the study. Lingyan Zheng and Baoli Wang have a substantial contribution to revise the article critically for important intellectual content and final approval of the version to be published. All authors read and approved the manuscript for submission.

Corresponding authors

Correspondence to Lingyan Zheng or Baoli Wang.

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Conflict of interests

The authors declare no potential conflicts of interest.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the Shanghai Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (Approval sequence: SH9H-2019-T159-2 and SH9H-2021-TK69-1).”

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10238_2022_939_MOESM4_ESM.tif

Additional file 4. Apoptosis evaluation of unactivated CD4+T cells treated with different concentration of KTC.(TIF 1339 KB)

10238_2022_939_MOESM5_ESM.tif

Additional file 5. Long-term treatment of KTC attenuates the symptoms of disease in SS-like NOD/ShiLtj mice. (A) Representative H&E staining of salivary gland tissues of the indicated groups. (B) Lymphocyte infiltration score of the indicated groups. Asterisk indicates P<0.05, double asterisks indicate P<0.01 vs. controlAdditional file 5. Long-term treatment of KTC attenuates the symptoms of disease in SS-like NOD/ShiLtj mice. (A) Representative H&E staining of salivary gland tissues of the indicated groups. (B) Lymphocyte infiltration score of the indicated groups. Asterisk indicates P<0.05, double asterisks indicate P<0.01 vs. control (TIF 3297 KB)

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Yin, J., Fu, J., Shao, Y. et al. CYP51-mediated cholesterol biosynthesis is required for the proliferation of CD4+ T cells in Sjogren’s syndrome. Clin Exp Med 23, 1691–1711 (2023). https://doi.org/10.1007/s10238-022-00939-5

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