Endoplasmic Reticulum Protein 72 Regulates Integrin Mac-1 Activity to Influence Neutrophil Recruitment-Reference-Cited by-全球学者库

Endoplasmic Reticulum Protein 72 Regulates Integrin Mac-1 Activity to Influence Neutrophil Recruitment

Published:2024-01-11 Issue: Volume: Page:
ISSN:1079-5642
Container-title:Arteriosclerosis, Thrombosis, and Vascular Biology
language:en
Short-container-title:ATVB

Author:

Li Yaofeng¹^ORCID,Xu Xulin¹²,Wang Haoqing Jerry³⁴^ORCID,Chen Yiyao Catherine³⁴,Chen Yaobing⁵,Chiu Joyce⁶^ORCID,Li Li¹^ORCID,Wang Lei¹,Wang Jinyu⁷⁸,Tang Zhaoming⁹^ORCID,Ren Lehao¹⁰^ORCID,Li Hongliang¹¹¹²^ORCID,Wang Xuanbin¹¹¹²^ORCID,Jin Si¹³^ORCID,Wu Yi¹⁴,Huang Mingdong¹⁵,Ju Lining Arnold³⁴^ORCID,Fang Chao¹²¹⁶^ORCID

Affiliation:

1. Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China. (Y.L., X.X., L.L., L.W., C.F.)

2. Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology, Wuhan, Hubei, China. (X.X., C.F.)

3. School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, New South Wales, Australia. (H.J.W., Y.C.C., L.A.J.)

4. The University of Sydney Nano Institute Sydney Nanoscience Hub, The University of Sydney, New South Wales, Australia. (H.J.W., Y.C.C., L.A.J.)

5. Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. (Y.C.)

6. Centenary Institute, The University of Sydney, New South Wales, Australia. (J.C.)

7. School of Stomatology, Tongji Medical Collage, Huazhong University of Science and Technology, Wuhan, Hubei, China. (J.W.)

8. Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration of Hubei Province, Wuhan, China (J.W.).

9. Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. (Z.T.)

10. Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. (L.R.)

11. Laboratory of Chinese Herbal Pharmacology, Department of Pharmacy, Renmin Hospital of Wuhan University, China (H.L., X.W.).

12. Biomedical Research Institute, School of Pharmaceutical Sciences and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China (H.L., X.W.).

13. Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. (S.J.)

14. Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu, China (Y.W.).

15. College of Chemistry, Fuzhou University, Fujian, China (M.H.).

16. The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (C.F.).

Abstract

BACKGROUND: Integrins mediate the adhesion, crawling, and migration of neutrophils during vascular inflammation. Thiol exchange is important in the regulation of integrin functions. ERp72 (ER-resident protein 72) is a member of the thiol isomerase family responsible for the catalysis of disulfide rearrangement. However, the role of ERp72 in the regulation of Mac-1 (integrin αMβ2) on neutrophils remains elusive. METHODS: Intravital microscopy of the cremaster microcirculation was performed to determine in vivo neutrophil movement. Static adhesion, flow chamber, and flow cytometry were used to evaluate in vitro integrin functions. Confocal fluorescent microscopy and coimmunoprecipitation were utilized to characterize the interactions between ERp72 and Mac-1 on neutrophil surface. Cell-impermeable probes and mass spectrometry were used to label reactive thiols and identify target disulfide bonds during redox exchange. Biomembrane force probe was performed to quantitatively measure the binding affinity of Mac-1. A murine model of acute lung injury induced by LPS was utilized to evaluate neutrophil-associated vasculopathy. RESULTS: ERp72-deficient neutrophils exhibited increased rolling but decreased adhesion/crawling on inflamed venules in vivo and defective static adhesion in vitro. The defect was due to defective activation of integrin Mac-1 but not LFA-1 (lymphocyte function-associated antigen-1) using blocking or epitope-specific antibodies. ERp72 interacted with Mac-1 in lipid rafts on neutrophil surface leading to the reduction of the C654-C711 disulfide bond in the αM subunit that is critical for Mac-1 activation. Recombinant ERp72, via its catalytic motifs, increased the binding affinity of Mac-1 with ICAM-1 (intercellular adhesion molecule-1) and rescued the defective adhesion of ERp72-deficient neutrophils both in vitro and in vivo. Deletion of ERp72 in the bone marrow inhibited neutrophil infiltration, ameliorated tissue damage, and increased survival during murine acute lung injury. CONCLUSIONS: Extracellular ERp72 regulates integrin Mac-1 activity by catalyzing disulfide rearrangement on the αM subunit and may be a novel target for the treatment of neutrophil-associated vasculopathy.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

Link

https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.123.319771