title: P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy.
abstract: Septic encephalopathy (SE) is a critical factor determining sepsis mortality. Vascular inflammation is known to be involved in SE, but the molecular events that lead to the development of encephalopathy remain unclear. Using time-lapse in vivo two-photon laser scanning microscopy, we provide the first direct evidence that cecal ligation and puncture in septic mice induces microglial trafficking to sites adjacent to leukocyte adhesion on inflamed cerebral microvessels. Our data further demonstrate that septic injury increased the chemokine CXCL1 level in brain endothelial cells by activating endothelial P2RX7 and eventually enhanced the binding of Mac-1 (CD11b/CD18)-expressing leukocytes to endothelial ICAM-1. In turn, leukocyte adhesion upregulated endothelial CX3CL1, thereby triggering microglia trafficking to the injured site. The sepsis-induced increase in endothelial CX3CL1 was abolished in CD18 hypomorphic mutant mice. Inhibition of the P2RX7 pathway not only decreased endothelial ICAM-1 expression and leukocyte adhesion but also prevented microglia overactivation, reduced brain injury, and consequently doubled the early survival of septic mice. These results demonstrate the role of the P2RX7 pathway in linking neurovascular inflammation to brain damage in vivo and provide a rationale for targeting endothelial P2RX7 for neurovascular protection during SE.
authors.affiliation: 1] Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China [2] Key Laboratory of Carbohydrate and Lipid Metabolism Research, College of Life Science and Technology, Dalian University, Dalian, Liaoning 116622, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Ling-Juan
authors.initials: LJ
authors.lastname: Hong
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Tao
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Tan
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Nan-Nan
authors.initials: NN
authors.lastname: Lu
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Cheng-Kun
authors.initials: CK
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Ahmed
authors.affiliation: School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, China.
authors.forename: Ying-Mei
authors.initials: YM
authors.lastname: Lu
authors.affiliation: Department of Neurology, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Liu
authors.affiliation: Department of Basic Sciences, Loma Linda University Health Schools of Medicine, Pharmacy, and Behavioral Health, Loma Linda, CA 92350, USA.
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Shi
authors.affiliation: Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: En-Yin
authors.initials: EY
authors.lastname: Lai
authors.affiliation: Hypertension, Kidney, and Vascular Research Center, Georgetown University Medical Center, Washington DC 20007, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Han
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D065166:Sepsis-Associated Encephalopathy / Q000378:metabolism* / Q000473:pathology
chemical_list: D016177:Macrophage-1 Antigen; C546469:P2rx7 protein, mouse; D058486:Receptors, Purinergic P2X7; D018799:Intercellular Adhesion Molecule-1