Xu Beibei, Li Hao, Zheng He, Gao Zhongyu, Miao Zhigang, Xu Xingshun, Yang Hao, Yang Yi
Departments of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Departments of Neurology, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Brain Behav Immun Health. 2024 Oct 18;42:100890. doi: 10.1016/j.bbih.2024.100890. eCollection 2024 Dec.
Interleukin 18 (IL-18), a proinflammatory cytokine, has been implicated in various neurological disorders, including cerebrovascular disease and psychiatric disorders. In a previous study, IL-18 was observed to activate microglia and enhance the inflammatory response following intracranial hemorrhage (ICH). However, the underlying mechanism remains unclear. In the present study, we found that IL-18 and IL-18 receptor (IL-18 R) are primarily secreted by neurons during the early stages after ICH, with microglia becoming the predominant source at 12-24 h after ICH. Meanwhile, the expression level of IL-18 R increased following ICH, along with an augmentation in the binding affinity of IL-18 R to IL-18. Subsequently, the deficiency of IL-18 R mitigated neurological impairment and subsequent activation of inflammatory pathways in mice post-ICH. Moreover, our findings suggest that IL-18-induced neurological injury after ICH may be mediated by the interaction between IL18R and NKCC1. Significantly, the NKCC1 inhibitor rescued the neurologic injury after ICH. In conclusion, our study suggests that targeting the IL-18/IL-18R/NKCC1 pathway could be an effective therapeutic strategy to attenuate secondary brain injury after ICH.
白细胞介素18（IL-18）是一种促炎细胞因子，与包括脑血管疾病和精神疾病在内的多种神经系统疾病有关。在先前的一项研究中，观察到IL-18在颅内出血（ICH）后可激活小胶质细胞并增强炎症反应。然而，其潜在机制仍不清楚。在本研究中，我们发现IL-18和IL-18受体（IL-18R）在ICH后的早期主要由神经元分泌，在ICH后12-24小时小胶质细胞成为主要来源。同时，ICH后IL-18R的表达水平增加，IL-18R与IL-18的结合亲和力也增强。随后，IL-18R的缺乏减轻了ICH后小鼠的神经功能损害以及随后炎症途径的激活。此外，我们的研究结果表明，ICH后IL-18诱导的神经损伤可能由IL18R和NKCC1之间的相互作用介导。重要的是，NKCC1抑制剂挽救了ICH后的神经损伤。总之，我们的研究表明，靶向IL-18/IL-18R/NKCC1途径可能是减轻ICH后继发性脑损伤的有效治疗策略。
