Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge.
Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge.
复制标题
DOI：
10.1177/1744806916647055
复制
发表时间：
2016
期刊：
影响因子：
3.3
通讯作者：
Lifshitz J
中科院分区：
文献类型：
--
作者：
Rowe RK;Ellis GI;Harrison JL;Bachstetter AD;Corder GF;Van Eldik LJ;Taylor BK;Marti F;Lifshitz J
伤害性疼痛和神经性疼痛作为人类创伤性脑损伤（TBI）后疾病过程的一部分而发生。中枢和外周炎症是创伤性脑损伤事件引发的主要继发性损伤过程，与外周伤害性疼痛的增强有关。我们推测，弥漫性创伤性脑损伤的炎症反应通过长期的免疫失调增强持续性疼痛。为了测试这一点，成年雄性C57BL/6小鼠经受中线液压冲击脑损伤或假手术。分析一组小鼠的皮质活检和血清中炎症相关细胞因子水平，沿着急性时间进程。在第二组中，在手术/损伤后7天用足底注射角叉菜胶诱导外周炎症。随后测量机械性痛觉过敏、胶质细胞酸性蛋白和脑中神经炎症的Iba1免疫组织化学分析，以及粘膜淋巴中T细胞分化的流式细胞术分析。创伤性脑损伤增加皮质和血清中的白细胞介素-6和趋化因子配体1水平，在1 - 9小时内达到峰值，然后消退。足底角叉菜胶产生的机械性痛觉过敏是由创伤性脑损伤增强。此外，来自脑损伤小鼠的粘膜T细胞在分化为炎症抑制调节性T细胞（Tcells）的能力方面表现出明显的缺陷。我们的结论是，创伤性脑损伤增加了炎症疼痛与皮肤炎症，有助于全身免疫失调。调节性T细胞是免疫抑制因子，T细胞不能分化成调节性T细胞导致不受调节的细胞因子产生，这可能有助于通过外周感觉神经元的兴奋增强外周疼痛。此外，调节性T细胞被鉴定为外周免疫稳态的治疗性再平衡的潜在靶点，以改善功能结果并降低创伤性脑损伤后外周炎性疼痛的发生率。
Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1–9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.