Abstract：
Repetitive exposure of innate immune cells to a subthreshold dosage of endotoxin components may modulate inflammatory responses. However, the regulatory mechanisms in the interactions between the central nervous system (CNS) and the immune system remain unclear. This study aimed to investigate the effects of lipopolysaccharide (LPS) preconditioning in repeated social defeat stress (RSDS)-induced abnormal immune responses and behavioral impairments. This study aimed to elucidate the mechanisms that underlie the protective effects of repeated administration of a subthreshold dose LPS on behavioral impairments using the RSDS paradigm. LPS preconditioning improved abnormal behaviors in RSDS-defeated mice, accompanied by decreased monoamine oxidases and increased glucocorticoid receptor expression in the hippocampus. In addition, pre-treated with LPS significantly decreased the recruited peripheral myeloid cells (CD11b+CD45hi), mainly circulating inflammatory monocytes (CD11b+CD45hiLy6ChiCCR2+) into the brain in response to RSDS challenge. Importantly, we found that LPS preconditioning exerts its protective properties by regulating lipocalin-2 (LCN2) expression in microglia, which subsequently induces expressions of chemokine CCL2 and pro-inflammatory cytokine. Subsequently, LPS-preconditioning lessened the resident microglia population (CD11b+CD45intCCL2+) in the brains of the RSDS-defeated mice. Moreover, RSDS-associated expressions of leukocytes (CD11b+CD45+CCR2+) and neutrophils (CD11b+CD45+Ly6G+) in the bone marrow, spleen, and blood were also attenuated by LPS-preconditioning. In particular, LPS preconditioning also promoted the expression of endogenous antioxidants and anti-inflammatory proteins in the hippocampus. Our results demonstrate that LPS preconditioning ameliorates lipocalin 2-associated microglial activation and aberrant immune response and promotes the expression of endogenous antioxidants and anti-inflammatory protein, thereby maintaining the homeostasis of pro-inflammation/anti-inflammation in both the brain and immune system, ultimately protecting the mice from RSDS-induced aberrant immune response and behavioral changes.
摘要：
先天性免疫细胞重复暴露于亚阈值剂量的内毒素组分可以调节炎症反应。然而,中枢神经系统（CNS）和免疫系统之间相互作用的调节机制尚不清楚。本研究旨在探讨脂多糖（LPS）预处理在反复社会失败应激（RSDS）诱导的异常免疫反应和行为障碍中的作用。这项研究旨在阐明使用RSDS范式重复施用亚阈值剂量LPS对行为障碍的保护作用的基础机制。LPS预处理改善RSDS失败小鼠的异常行为，伴随着海马中单胺氧化酶的减少和糖皮质激素受体表达的增加。此外,用LPS预处理显著减少募集的外周骨髓细胞（CD11b+CD45hi），主要循环炎性单核细胞(CD11b+CD45hiLy6ChiCCR2+)进入脑以响应RSDS攻击。重要的是,我们发现LPS预处理通过调节小胶质细胞脂质运载蛋白-2(LCN2)的表达发挥其保护作用,随后诱导趋化因子CCL2和促炎细胞因子的表达。随后，LPS预处理减少了RSDS失败小鼠大脑中的常驻小胶质细胞数量（CD11bCD45intCCL2）。此外，骨髓中白细胞(CD11b+CD45+CCR2+)和中性粒细胞(CD11b+CD45+Ly6G+)的RSDS相关表达,脾,脾和血液也通过LPS预处理减毒。特别是,LPS预处理还促进海马内源性抗氧化剂和抗炎蛋白的表达。我们的结果表明，LPS预处理可以改善脂质运载蛋白2相关的小胶质细胞活化和异常免疫反应，并促进内源性抗氧化剂和抗炎蛋白的表达。从而维持大脑和免疫系统中促炎症/抗炎症的稳态，最终保护小鼠免受RSDS诱导的异常免疫应答和行为改变。
