Exposure to X-rays Causes Depression-like Behaviors in Mice via HMGB1-mediated Pyroptosis

• Published in: Neuroscience Vol. 481; pp. 99 - 110
• Main Authors: Xu, Lixing, Huang, Haiqin, Liu, Tianqing, Yang, Tao, Yi, Xuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 15.01.2022
• Subjects: Animals; Depression; depression-like behaviors; HMGB1; HMGB1 Protein - metabolism; Humans; Inflammasomes - metabolism; Mice; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; pyroptosis; Pyroptosis - physiology; radiation brain injury; X-Rays; GSDMD; AD; BBB; FST; CUMS; CNS; HMGB1; DAMPs; PFD; PRP; ASC; pyroptosis; OPT; RD; AIM2; radiation brain injury; depression-like behaviors; TST; Gly; SPT; ROS; RBI; PAMPs; NLRP3
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2021.11.023

[Display omitted] •X-rays caused the depression-like behaviors, microglial activation, and neuronal apoptosis in mice.•ROS production and overexpression of HMGB1 from neurons participated in radiation-induced brain damage.•NLRP3/ASC/Caspase-1-mediated microglial pyroptosis contributed to neuronal damage after X-ray challenge. The widespread application of ionizing radiation in industrial and medical fields leads to the increased brain exposure to X-rays. Radiation brain injury (RBI) seriously affects health of patients by causing cognitive dysfunction and neuroinflammation. However, the link between X-ray exposure and depressive symptoms and their detailed underlying mechanisms have not been well studied. Herein, we investigated the potential depression-like behaviors in mice exposed to X-rays and then explored the role of HMGB1 in this injury. We found that X-ray stimulation induced the generation of reactive oxygen species (ROS) in the prefrontal cortex in a dose-dependent manner, leading to the occurrence of depression-like behaviors of the mice. Moreover, X-ray exposure increased the expression of HMGB1, activated NLRP3 inflammasome signaling pathway and microglial cells, and then facilitated the release of pro-inflammatory cytokines, resulting in the pyroptosis and neuron loss both in vivo and in vitro. Additionally, glycyrrhizin (Gly), which is a HMGB1 inhibitor, reversed X-ray-induced behavioral changes and neuronal damage. Our findings indicated that HMGB1-mediated pyroptosis was involved in radiation-induced depression.