Interleukin-33 Knockout Promotes High Mobility Group Box 1 Release from Astrocytes by Acetylation Mediated by P300/CBP-Associated Factor in Experimental Autoimmune Encephalomyelitis
Yifan Xiao1,2,3 · Liyan Hao1,2,3 · Xinyi Cao1,3 · Yibo Zhang1,3 · Qingqing Xu1,3 · Luyao Qin1,3 · Yixuan Zhang1,3 · Yangxingzi Wu1,3 · Hongyan Zhou1,2,3 · Mengjuan Wu1,2,3 · Mingshan Pi1,3 · Qi Xiong1,3 · Youhua Yang1,3 · Yuran Gui1,3 · Wei Liu1,2,3 · Fang Zheng4,5 · Xiji Shu1,2,3 · Yiyuan Xia1,2,31 Hubei Key Laboratory of Cognitive and Afective Disorders, Jianghan University, Wuhan 430056, Hubei, China
2 Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan 430056, Hubei, China
3 Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, Hubei, China
4 Department of Immunology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
5 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
Abstract
High mobility group box 1 (HMGB1), when released extracellularly, plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system. In experimental autoimmune encephalomyelitis (EAE), a condition that models multiple sclerosis, the levels of extracellular HMGB1 and interleukin-33 (IL-33) have been found to be inversely correlated. However, the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive. Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes, upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice. Conversely, the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes. These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
Keywords
Interleukin-33; High mobility group box 1; P300/CBP-associated factor; Astrocytes; Experimental autoimmune encephalomyelitis
