Fonken Laura K, Frank Matthew G, Kitt Meagan M, D'Angelo Heather M, Norden Diana M, Weber Michael D, Barrientos Ruth M, Godbout Jonathan P, Watkins Linda R, Maier Steven F
Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and
Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and.
J Neurosci. 2016 Jul 27;36(30):7946-56. doi: 10.1523/JNEUROSCI.1161-16.2016.
Amplified neuroinflammatory responses following an immune challenge occur with normal aging and can elicit or exacerbate neuropathology. The mechanisms mediating this sensitized or "primed" immune response in the aged brain are not fully understood. The alarmin high mobility group box 1 (HMGB1) can be released under chronic pathological conditions and initiate inflammatory cascades. This led us to investigate whether HMGB1 regulates age-related priming of the neuroinflammatory response. Here, we show that HMGB1 protein and mRNA were elevated in the hippocampus of unmanipulated aged rats (24-month-old F344XBN rats). Furthermore, aged rats had increased HMGB1 in the CSF, suggesting increased HMGB1 release. We demonstrate that blocking HMGB1 signaling with an intracisterna magna (ICM) injection of the competitive antagonist to HMGB1, Box-A, downregulates basal expression of several inflammatory pathway genes in the hippocampus of aged rats. This indicates that blocking the actions of HMGB1 might reduce age-associated inflammatory priming. To test this hypothesis, we evaluated whether HMGB1 antagonism blocks the protracted neuroinflammatory and sickness response to peripheral Escherichia coli (E. coli) infection in aged rats. ICM pretreatment of aged rats with Box-A 24 h before E. coli infection prevented the extended hippocampal cytokine response and associated cognitive and affective behavioral changes. ICM pretreatment with Box-A also inhibited aging-induced potentiation of the microglial proinflammatory response to lipopolysaccharide ex vivo Together, these results suggest that HMGB1 mediates neuroinflammatory priming in the aged brain. Blocking the actions of HMGB1 appears to "desensitize" aged microglia to an immune challenge, thereby preventing exaggerated behavioral and neuroinflammatory responses following infection.
The world's population is aging, highlighting a need to develop treatments that promote quality of life in aged individuals. Normal aging is associated with precipitous drops in cognition, typically following events that induce peripheral inflammation (e.g., infection, surgery, heart attack). Peripheral immune stimuli cause exaggerated immune responses in the aged brain, which likely underlie these behavioral deficits. Here, we investigated whether the alarmin high mobility group box 1 (HMGB1) mediates age-associated "priming" of the neuroinflammatory response. HMGB1 is elevated in aged rodent brain and CSF. Blocking HMGB1 signaling downregulated expression of inflammatory pathway genes in aged rat brain. Further, HMGB1 antagonism prevented prolonged infection-induced neuroinflammatory and sickness responses in aged rats. Overall, blocking HMGB1 "desensitized" microglia in the aged brain, thereby preventing pathological infection-elicited neuroinflammatory responses.
免疫挑战后放大的神经炎症反应在正常衰老过程中会出现，并可引发或加剧神经病理学变化。介导老年大脑中这种致敏或“预激”免疫反应的机制尚未完全了解。警报素高迁移率族蛋白B1（HMGB1）可在慢性病理条件下释放，并启动炎症级联反应。这促使我们研究HMGB1是否调节与年龄相关的神经炎症反应预激。在此，我们表明，在未处理的老年大鼠（24月龄F344XBN大鼠）海马中，HMGB1蛋白和mRNA水平升高。此外，老年大鼠脑脊液中的HMGB1增加，表明HMGB1释放增加。我们证明，通过脑池内注射HMGB1竞争性拮抗剂Box-A阻断HMGB1信号传导，可下调老年大鼠海马中几种炎症通路基因的基础表达。这表明阻断HMGB1的作用可能会减少与年龄相关的炎症预激。为了验证这一假设，我们评估了HMGB1拮抗剂是否能阻断老年大鼠对周围大肠杆菌（E. coli）感染的持久神经炎症和疾病反应。在大肠杆菌感染前24小时用Box-A对老年大鼠进行脑池内预处理，可预防海马细胞因子反应延长以及相关的认知和情感行为变化。用Box-A进行脑池内预处理还能抑制衰老诱导的小胶质细胞对脂多糖体外促炎反应的增强。总之，这些结果表明HMGB1介导老年大脑中的神经炎症预激。阻断HMGB1的作用似乎使老年小胶质细胞对免疫挑战“脱敏”，从而预防感染后过度的行为和神经炎症反应。
世界人口正在老龄化，这凸显了开发促进老年人生活质量的治疗方法的必要性。正常衰老与认知能力急剧下降有关，通常发生在诱发外周炎症的事件之后（如感染、手术、心脏病发作）。外周免疫刺激会在老年大脑中引发过度的免疫反应，这可能是这些行为缺陷的潜在原因。在此，我们研究了警报素高迁移率族蛋白B1（HMGB1）是否介导与年龄相关的神经炎症反应“预激”。HMGB1在老年啮齿动物的大脑和脑脊液中升高。阻断HMGB1信号传导可下调老年大鼠大脑中炎症通路基因的表达。此外，HMGB1拮抗剂可预防老年大鼠因感染引起的持久神经炎症和疾病反应。总体而言，阻断HMGB1可使老年大脑中的小胶质细胞“脱敏”，从而预防病理性感染引发神经炎症反应。
