Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran.
Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Brain Res Bull. 2022 Jul;185:74-85. doi: 10.1016/j.brainresbull.2022.04.013. Epub 2022 May 4.
Mounting evidence indicates that sepsis can induce long-lasting brain dysfunction. Recently, it has been proposed that the brain may become more sensitive to systemic inflammation if microglial cells are already primed. Microglial priming has been demonstrated in aging, traumatic brain injury, and neurodegenerative diseases. There is evidence suggesting that systemic inflammation may also prime microglia. This study aimed to investigate the brain's response to a second immune challenge in sepsis survivors and the possible role of microglial priming.
Adult BALB/c mice were intraperitoneally (ip) injected with 5 mg/kg lipopolysaccharide (LPS) for sepsis induction. One month later, mice received a second immune challenge (LPS, 0.33 mg/kg). A cohort of mice was sacrificed 2 h post-LPS injection to measure inflammatory mediators mRNA expression. The second cohort of mice was tested on a battery of behavioral tests and then sacrificed, and brain tissues were removed for biochemical analyses.
Results showed that in septic mice, secondary LPS challenge induced heightened neuroinflammation compared to the control mice, as evident by a significant increase of IL-1β, TNF-α, and iNOS mRNA expression. In the immunochallenged septic mice, the anti-inflammatory cytokine IL-10 expression was also significantly increased compared to the control mice. Sepsis induction significantly disrupted the recognition ability in the novel object recognition, but the second immune challenge had no significant effect. However, immunochallenged septic mice exhibited more anxiety-like behavior in the marble burying task and intensive depressive-like behavior in the forced swim test. Additionally, the second immune challenge reduced arginase-1 levels in septic but not control mice. On the other hand, CIITA levels were increased more significantly in the LPS injected control mice compared to septic mice. Neither sepsis nor the second immune challenge significantly affected inhibitory avoidance behavior and Aβ levels in brain tissue.
Our finding suggests that low-grade immune challenge can induce exacerbated behavioral change and exaggerated inflammatory response in the brain of post-septic mice.
越来越多的证据表明，败血症可导致持久的脑功能障碍。最近有研究提出，如果小胶质细胞预先被激活，大脑可能会对全身炎症更敏感。在衰老、创伤性脑损伤和神经退行性疾病中已经证明了小胶质细胞的预激活。有证据表明，全身炎症也可能预先激活小胶质细胞。本研究旨在探讨败血症幸存者大脑对第二次免疫挑战的反应以及小胶质细胞预激活的可能作用。
成年 BALB/c 小鼠经腹腔内注射 5mg/kg 脂多糖（LPS）诱导败血症。一个月后，小鼠接受第二次免疫挑战（LPS，0.33mg/kg）。一组小鼠在 LPS 注射后 2 小时处死，以测量炎症介质 mRNA 表达。第二组小鼠进行一系列行为测试，然后处死，取出脑组织进行生化分析。
结果表明，在败血症小鼠中，与对照组相比，第二次 LPS 挑战引起了更高的神经炎症，这表现在 IL-1β、TNF-α 和 iNOS mRNA 表达显著增加。在免疫挑战的败血症小鼠中，抗炎细胞因子 IL-10 的表达也明显高于对照组。败血症诱导显著破坏了新物体识别能力，但第二次免疫挑战没有显著影响。然而，免疫挑战的败血症小鼠在大理石埋藏任务中表现出更多的焦虑样行为，在强迫游泳试验中表现出更强烈的抑郁样行为。此外，第二次免疫挑战降低了败血症小鼠但没有降低对照组小鼠的精氨酸酶-1 水平。另一方面，与败血症小鼠相比，LPS 注射的对照组小鼠的 CIITA 水平增加更为显著。败血症或第二次免疫挑战均未显著影响大脑中的抑制性回避行为和 Aβ 水平。
我们的发现表明，低水平的免疫挑战可导致败血症后小鼠大脑中行为变化加剧和炎症反应过度。
