单位：[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[2]Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.[3]School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, New South Wales, Australia[4]The University of Sydney Nano Institute Sydney Nanoscience Hub, The University of Sydney, New South Wales, Australia[5]Institute of Pathology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China病理研究所华中科技大学同济医学院附属同济医院病理科[6]Centenary Institute, The University of Sydney, New South Wales, Australia[7]School of Stomatology, Tongji Medical Collage, Huazhong University of Science and Technology, Wuhan, Hubei, China.[8]Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration of Hubei Province, Wuhan, China[9]Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.华中科技大学同济医学院附属协和医院[10]Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.华中科技大学同济医学院附属协和医院[11]Laboratory of Chinese Herbal Pharmacology, Department of Pharmacy, Renmin Hospital of Wuhan University, China[12]Biomedical Research Institute, School of Pharmaceutical Sciences and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China[13]Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.[14]Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu, China[15]College of Chemistry, Fuzhou University, Fujian, China[16]The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
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.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.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.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.
基金：
This work was supported, in part, by the National Natural Science Foundation of
China (921691 14 and 81 802932), the Natural Science Fund for Distinguished
Young Scholars of Hubei Province (2022CFA054), the National Key R&D Program
of China (201 8YFE0113600), the Global Research Award and the Supplement
Award from the American Society of Hematology, a HUST-QMUL joint research grant (2022-HUST-QMUL-SPRF-01), a HUST-USYD-JRC grant, the Open Proj-
ect of Hubei Key L .aboratory of Wudang L ocal Chinese Medicine Research from
the Hubei University of Medicine (WDCM2023001/2022001), National Health
and Medical Research Council of Australia Ideas Grant (APP2003904) and an
NSW Cardiovascular Capacity Building Program Early-Mid Career Researcher
Grant. L Arnold Ju is an Australian Heart Foundation Future L eader Fellow L evel
2 (105863) and a Snow Medical Research Foundation Fellow (2022SF176).
第一作者单位：[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
共同第一作者：
通讯作者：
通讯机构：[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[2]Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.[16]The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China[*1]Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, Hubei 430030, China. Email f
推荐引用方式(GB/T 7714)：
Li Yaofeng,Xu Xulin,Wang Haoqing Jerry,et al.Endoplasmic Reticulum Protein 72 Regulates Integrin Mac-1 Activity to Influence Neutrophil Recruitment[J].ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY.2024,44(3):E82-E98.doi:10.1161/ATVBAHA.123.319771.
APA：
Li Yaofeng,Xu Xulin,Wang Haoqing Jerry,Chen Yiyao Catherine,Chen Yaobing...&Fang Chao.(2024).Endoplasmic Reticulum Protein 72 Regulates Integrin Mac-1 Activity to Influence Neutrophil Recruitment.ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY,44,(3)
MLA：
Li Yaofeng,et al."Endoplasmic Reticulum Protein 72 Regulates Integrin Mac-1 Activity to Influence Neutrophil Recruitment".ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 44..3(2024):E82-E98
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