Dipeptidyl Peptidase 4/Midline‐1 Axis Promotes T Lymphocyte Motility in Atherosclerosis

Author:

Rao Xiaoquan12,Razavi Michael2,Mihai Georgeta3,Wei Yingying2,Braunstein Zachary4,Frieman Matthew B.5,Sun Xiao Jian6,Gong Quan7,Chen Jun8,Zhao Gang9,Liu Zheng1011,Quon Michael J.6,Dong Lingli12,Rajagopalan Sanjay2,Zhong Jixin241112ORCID

Affiliation:

1. Division of Cardiology Department of Internal Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 P. R. China

2. Cardiovascular Research Institute Case Western Reserve University Cleveland Ohio 44106 USA

3. Brigham and Women's Hospital Harvard Medical School Boston Massachusetts 02115 USA

4. Wexner Medical Center The Ohio State University Columbus Ohio 43210 USA

5. Department of Microbiology and Immunology University of Maryland School of Medicine Baltimore Maryland 21201 USA

6. Department of Medicine University of Maryland School of Medicine Baltimore Maryland 21201 USA

7. Department of Immunology School of Medicine Yangtze University Jingzhou Hubei 434023 P. R. China

8. Sinopharm Dongfeng General Hospital Hubei University of Medicine Shiyan Hubei 442008 P. R. China

9. Department of Cardiology Shandong Provincial Hospital affiliated to Shandong University Jinan Shandong 250021 P. R. China

10. Department of Otolaryngology‐Head and Neck Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 P. R. China

11. Institute of Allergy and Clinical Immunology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 P. R. China

12. Division of Rheumatology and Immunology Department of Internal Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 P. R. China

Abstract

AbstractT cells play a crucial role in atherosclerosis, with its infiltration preceding the formation of atheroma. However, how T‐cell infiltration is regulated in atherosclerosis remains largely unknown. Here, this work demonstrates that dipeptidyl peptidase‐4 (DPP4) is a novel regulator of T‐cell motility in atherosclerosis. Single‐cell ribonucleic acid (RNA) sequencing and flow cytometry show that CD4+ T cells in atherosclerotic patients display a marked increase of DPP4. Lack of DPP4 in hematopoietic cells or T cells reduces T‐cell infiltration and atherosclerotic plaque volume in atherosclerosis mouse models. Mechanistically, DPP4 deficiency reduces T‐cell motility by suppressing the expression of microtubule associated protein midline‐1 (Mid1) in T cells. Deletion of either DPP4 or Mid1 inhibits chemokine‐induced shape change and motility, while restitution of Mid1 in Dpp4−/− T cell largely restores its migratory ability. Thus, DPP4/Mid1, as a novel regulator of T‐cell motility, may be a potential inflammatory target in atherosclerosis.

Funder

National Natural Science Foundation of China

National Institutes of Health

American Heart Association

National Key Research and Development Program of China

American Association of Immunologists

American Diabetes Association

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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