Recent years have seen an explosion of research pertaining to biological psychiatry, yet despite subsequent advances in our understanding of neuroimmune communication pathways, how the brain senses and responds to peripheral inflammation remains poorly understood. A better understanding of these pathways may be important for generating novel therapeutics to treat many patients with chronic inflammatory diseases who also suffer from neuropsychiatric comorbidities. Here we have systematically assessed the leukocyte infiltrate to the brain following systemic endotoxin exposure to better understand this novel route of neuroimmune communication. Mice were injected intraperitoneally with LPS daily for 2, 5 or 7 consecutive days. We systematically interrogated the subsequent induction of chemokine transcription in the brain using TaqMan low-density arrays. A combination of flow cytometry and immunohistochemistry was then used to characterise the accompanying leukocyte infiltrate. Repeated LPS challenges resulted in prolonged activation of brain-resident microglia, coupled with an increased local transcription of numerous chemokines. After 2 days of administering LPS, there was a marked increase in the expression of the neutrophil chemoattractants CXCL1 and CXCL2; the monocyte chemoattractants CCL2, CCL5, CCL7 and CCL8; and the lymphocyte chemoattractants CXCL9, CXCL10 and CXCL16. In a number of cases, this response was sustained for several days. Chemokine induction was associated with a transient recruitment of neutrophils and monocytes to the brain, coupled with a sustained accumulation of macrophages, CD8+ T cells, NK cells and NKT cells. Strikingly, neutrophils, monocytes and T cells appeared to extravasate from the vasculature and/or CSF to infiltrate the brain parenchyma. Prolonged exposure to a peripheral inflammatory stimulus triggers the recruitment of myeloid cells and lymphocytes to the brain. By altering the inflammatory or metabolic milieu of the brain, this novel method of immune-to-brain communication may have profound implications for patients with chronic inflammatory diseases, potentially leading to neuropsychiatric comorbidities.

中文翻译：

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持续暴露于全身性内毒素会触发大脑中的趋化因子诱导，随后白细胞快速流入

近年来，与生物精神病学有关的研究呈爆炸式增长，然而，尽管我们对神经免疫通讯通路的理解随后取得了进展，但大脑如何感知和响应外周炎症仍然知之甚少。更好地了解这些途径可能对于产生新的疗法来治疗许多患有慢性炎症性疾病的患者也很重要，这些患者也患有神经精神疾病。在这里，我们系统地评估了全身性内毒素暴露后白细胞浸润到大脑中的情况，以更好地了解这种新的神经免疫通讯途径。每天连续 2、5 或 7 天给小鼠腹膜内注射 LPS。我们使用 TaqMan 低密度阵列系统地询问了随后在大脑中对趋化因子转录的诱导。然后使用流式细胞术和免疫组织化学的组合来表征伴随的白细胞浸润。反复的 LPS 挑战导致大脑驻留小胶质细胞的激活时间延长，以及许多趋化因子的局部转录增加。LPS给药2天后，中性粒细胞趋化因子CXCL1和CXCL2的表达明显增加；单核细胞趋化因子CCL2、CCL5、CCL7和CCL8；以及淋巴细胞趋化因子CXCL9、CXCL10和CXCL16。在许多情况下，这种反应持续了好几天。趋化因子诱导与中性粒细胞和单核细胞向大脑的短暂募集有关，再加上巨噬细胞、CD8+ T 细胞、NK 细胞和 NKT 细胞的持续积累。引人注目的是，嗜中性粒细胞、单核细胞和 T 细胞似乎从脉管系统和/或脑脊液中渗出以渗入脑实质。长时间暴露于外周炎症刺激会触发骨髓细胞和淋巴细胞向大脑的募集。通过改变大脑的炎症或代谢环境，这种新的免疫-大脑交流方法可能对患有慢性炎症性疾病的患者产生深远的影响，可能导致神经精神合并症。长时间暴露于外周炎症刺激会触发骨髓细胞和淋巴细胞向大脑的募集。通过改变大脑的炎症或代谢环境，这种新的免疫-大脑交流方法可能对患有慢性炎症性疾病的患者产生深远的影响，可能导致神经精神合并症。长时间暴露于外周炎症刺激会触发骨髓细胞和淋巴细胞向大脑的募集。通过改变大脑的炎症或代谢环境，这种新的免疫-大脑交流方法可能对患有慢性炎症性疾病的患者产生深远的影响，可能导致神经精神合并症。