Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
J Immunol. 2018 May 1;200(9):3188-3200. doi: 10.4049/jimmunol.1700834. Epub 2018 Mar 21.
Sepsis commonly results in acute and chronic brain dysfunction, which dramatically increases the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. However, we have found previously that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. In this article, we show that S100A8/A9 is increased in the brains of patients who died of sepsis and that S100A8 is expressed in astrocytes and myeloid cells. Using a mouse model of sepsis survival, we show that S100A8/A9 is persistently expressed in the brain after sepsis. expression is necessary for recruitment of neutrophils to the brain and for priming production of reactive oxygen species and TNF-α secretion in microglia and macrophages. However, despite improving these indices of chronic inflammation, deficiency results in worsened anxiety-like behavior 2 wk after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial-reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors.
败血症通常会导致急性和慢性脑功能障碍，这极大地增加了这种常见疾病相关的发病率。败血症存活动物模型中的慢性脑功能障碍与持续的神经炎症和多种细胞因子的表达有关。然而，我们之前发现，小胶质细胞在败血症后主要上调损伤相关分子 S100A8/A9。在本文中，我们表明，死于败血症的患者大脑中 S100A8/A9 增加，并且 S100A8 在星形胶质细胞和髓样细胞中表达。使用败血症存活的小鼠模型，我们表明 S100A8/A9 在败血症后持续在大脑中表达。S100A8/A9 的表达对于中性粒细胞向大脑的募集以及小胶质细胞和巨噬细胞中活性氧和 TNF-α 分泌的引发是必需的。然而，尽管改善了这些慢性炎症指标，S100A8 缺乏会导致败血症后 2 周焦虑样行为恶化。综上所述，这些结果表明 S100A8/A9 有助于败血症存活小鼠的几种神经炎症方面，包括粒细胞募集和小胶质细胞活性氧和细胞因子产生的引发，并且这些过程可能对败血症存活者的焦虑行为具有保护作用。
