Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA.
Neurobiol Aging. 2019 May;77:194-206. doi: 10.1016/j.neurobiolaging.2019.02.010. Epub 2019 Feb 20.
After traumatic brain injury (TBI), individuals aged over 65 years show increased mortality and worse functional outcomes compared with younger persons. As neuroinflammation is a key pathobiological mechanism of secondary injury after TBI, we examined how aging affects post-traumatic microglial responses and functional outcomes. Young (3-month-old) and aged (18-month-old) male C57Bl/6 mice were subjected to moderate-level controlled cortical impact or sham surgery, and neurological function was evaluated. At 72 hours after injury, brain, blood, and spleen leukocyte counts were assessed ex vivo using flow cytometry. Aged mice demonstrated more severe deficits in forelimb grip strength, balance and motor coordination, spontaneous locomotor activity, and anxiety-like behavior. These animals also exhibited more robust microglial proliferation and significantly higher numbers of brain-infiltrating leukocytes. Microglia in aged mice showed impairments in phagocytic activity and higher production of interleukin-1β (IL-1β). Infiltrating myeloid cells in aged TBI mice also had deficits in phagocytosis but showed diminished proinflammatory cytokine production and greater reactive oxygen species production. Expression of several senescence markers (Bcl-2, p16, p21, lipofuscin, and H2AX [pS139]) was increased with age and/or TBI in both microglia and injured cortex. Although there was no difference in the number of circulating blood neutrophils as a function of age, young mice exhibited more pronounced TBI-induced splenomegaly and splenic myeloid cell expansion. Thus, worse post-traumatic behavioral outcomes in aged animals are associated with exaggerated microglial responses, increased leukocyte invasion, and upregulation of senescence markers.
在创伤性脑损伤（TBI）后，与年轻人相比，年龄超过 65 岁的个体死亡率更高，功能结局更差。由于神经炎症是 TBI 后继发性损伤的关键病理生物学机制，我们研究了衰老如何影响创伤后小胶质细胞的反应和功能结局。将年轻（3 个月大）和老年（18 个月大）雄性 C57Bl/6 小鼠进行中度控制皮质撞击或假手术，并评估神经功能。在损伤后 72 小时，使用流式细胞术在体外评估大脑、血液和脾脏白细胞计数。老年小鼠在前肢握力、平衡和运动协调、自发运动活动和焦虑样行为方面表现出更严重的缺陷。这些动物还表现出更强的小胶质细胞增殖和明显更高数量的脑浸润白细胞。老年小鼠的小胶质细胞吞噬活性受损，白细胞介素-1β（IL-1β）的产生量更高。老年 TBI 小鼠浸润的髓样细胞吞噬作用也存在缺陷，但促炎细胞因子的产生减少，活性氧的产生增加。衰老标志物（Bcl-2、p16、p21、脂褐素和 H2AX[pS139]）的表达随年龄和/或 TBI 在小胶质细胞和损伤皮质中增加。尽管循环血液中性粒细胞的数量随年龄变化没有差异，但年轻小鼠表现出更明显的 TBI 诱导的脾肿大和脾髓样细胞扩张。因此，老年动物创伤后行为结局较差与过度的小胶质细胞反应、白细胞浸润增加和衰老标志物的上调有关。
