Volume 25, No 6, Jun 2015

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 25 Issue 6, June 2015: 674-690   |  Open Access

ORIGINAL ARTICLES

P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy

Huan Wang^1,2,*, Ling-Juan Hong^1,*, Ji-Yun Huang^1,*, Quan Jiang¹, Rong-Rong Tao¹, Chao Tan¹, Nan-Nan Lu¹, Cheng-Kun Wang¹, Muhammad M Ahmed¹, Ying-Mei Lu³, Zhi-Rong Liu⁴, Wei-Xing Shi⁵, En-Yin Lai⁶, Christopher S Wilcox⁷ and Feng Han¹

¹Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
²Key Laboratory of Carbohydrate and Lipid Metabolism Research, College of Life Science and Technology, Dalian University, Dalian, Liaoning 116622, China
³School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, China
⁴Department of Neurology, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310009, China
⁵Department of Basic Sciences, Loma Linda University Health Schools of Medicine, Pharmacy, and Behavioral Health, Loma Linda, CA 92350, USA
⁶Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
⁷Hypertension, Kidney, and Vascular Research Center, Georgetown University Medical Center, Washington DC 20007, USA Correspondence: Feng Han ;(changhuahan@zju.edu.cn)

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.

10.1038/cr.2015.61

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