Neuroscience Center, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
J Cereb Blood Flow Metab. 2019 Nov;39(11):2196-2209. doi: 10.1177/0271678X18786633. Epub 2018 Jul 13.
Repetitive mild traumatic brain injury during adolescence can induce neurological dysfunction through undefined mechanisms. Interleukin-1 (IL-1) contributes to experimental adult diffuse and contusion TBI models, and IL-1 antagonists have entered clinical trials for severe TBI in adults; however, no such data exist for adolescent TBI. We developed an adolescent mouse repetitive closed head injury (rCHI) model to test the role of IL-1 family members in post-injury neurological outcome. Compared to one CHI, three daily injuries (3HD) produced acute and chronic learning deficits and emergence of hyperactivity, without detectable gliosis, neurodegeneration, brain atrophy, and white matter loss at one year. Mature IL-1β and IL-18 were induced in brain endothelium in 3HD but not 1HD, three hit weekly, or sham animals. IL-1β processing was induced cell-autonomously in three-dimensional human endothelial cell cultures subjected to in vitro concussive trauma. Mice deficient in IL-1 receptor-1 or caspase-1 had improved post-injury Morris water maze performance. Repetitive mild CHI in adolescent mice may induce behavioral deficits in the absence of significant histopathology. The endothelium is a potential source of IL-1β and IL-18 in rCHI, and IL-1 family members may be therapeutic targets to reduce or prevent neurological dysfunction after repetitive mild TBI in adolescents.
青少年时期反复发生的轻度创伤性脑损伤可能通过未明机制引起神经功能障碍。白细胞介素-1（IL-1）有助于实验性成年弥漫性和挫伤性 TBI 模型，IL-1 拮抗剂已进入成人严重 TBI 的临床试验；然而，青少年 TBI 则没有此类数据。我们开发了一种青少年小鼠反复闭合性颅脑损伤（rCHI）模型，以测试 IL-1 家族成员在损伤后神经功能结果中的作用。与单次脑损伤（1HD）相比，3 次每日损伤（3HD）导致急性和慢性学习能力下降以及活动过度，在 1 年时没有检测到神经胶质增生、神经退行性变、脑萎缩和白质丢失。在 3HD 中但不在 1HD、每周 3 次打击或假手术动物中诱导脑内皮细胞成熟的 IL-1β 和 IL-18。在体外受到震荡性创伤的三维人内皮细胞培养物中，IL-1β 处理是自主诱导的。缺乏 IL-1 受体-1 或半胱天冬酶-1 的小鼠在损伤后 Morris 水迷宫表现更好。青少年小鼠的反复轻度 CHI 可能会在没有明显组织病理学的情况下引起行为缺陷。内皮细胞是 rCHI 中 IL-1β 和 IL-18 的潜在来源，IL-1 家族成员可能是减少或预防青少年反复轻度 TBI 后神经功能障碍的治疗靶点。
