HMGB1 from Astrocytes Promotes EAE by Influencing the Immune Cell Infiltration-Associated Functions of BMECs in Mice
Junyu Shi1 • Yifan Xiao3 • Na Zhang1 • Mengya Jiao1 • Xuhuan Tang1 • Chan Dai1 • Chenchen Wang1 • Yong Xu1 • Zheng Tan1,2 • Feili Gong1 • Fang Zheng1,21 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2 Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
3 Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan 430056, China
Abstract
High mobility group box 1 (HMGB1) has been reported to play an important role in experimental autoimmune encephalomyelitis (EAE). Astrocytes are important components of neurovascular units and tightly appose the endothelial cells of microvessels by their perivascular endfeet and directly regulate the functions of the blood-brain barrier. Astrocytes express more HMGB1 during EAE while the exact roles of astrocytic HMGB1 in EAE have not been well elucidated. Here, using conditional-knockout mice, we found that astrocytic HMGB1 depletion decreased morbidity, delayed the onset time, and reduced the disease score and demyelination of EAE. Meanwhile, there were fewer immune cells, especially pathogenic T cells infiltration in the central nervous system of astrocytic HMGB1 conditional-knockout EAE mice, accompanied by up-regulated expression of the tight-junction protein Claudin5 and down-regulated expression of the cell adhesion molecules ICAM1 and VCAM1 in vivo. In vitro, HMGB1 released from astrocytes decreased Claudin5 while increased ICAM1 and VCAM1 expressed by brain microvascular endothelial cells (BMECs) through TLR4 or RAGE. Taken together, our results demonstrate that HMGB1 derived from astrocytes aggravates EAE by directly influencing the immune cell infiltration-associated functions of BMECs.
Keywords
HMGB1; Astrocytes; Experimental autoimmune encephalomyelitis; Blood-brain barrier
