Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies. This disease causes disabling neuropsychiatric symptoms even in the absence of apparent inflammation in the central nervous system (CNS), but the mechanisms involved remain unknown. Innate immune-mediated inflammation has attracted attention as a pathogenic mechanism in neuropsychiatric diseases. We investigated the CNS of lupus-prone mice focusing on innate immunity. Three strains of lupus-prone mice, FcγRIIB−/−Yaa, an F1 hybrid of NZB and NZW (NZB/NZW) mice, and MRL/Faslpr (MRL/lpr) mice were used to analyze CNS immunopathology. Flow cytometry analysis demonstrated the numbers of brain CD45+ cells were increased compared with controls in lupus-prone mice. Upregulation of MHC class I and PDCA1 was observed in microglia and CD11b+ myeloid cells of lupus-prone mice, indicating they were activated in response to interferons (IFN). Microglial gene expression analysis of FcγRIIB−/−Yaa mice revealed the upregulation of IFN-responsive genes and inflammation-related genes including Axl, Clec7a, and Itgax, which were previously reported in neurodegenerative conditions and primed conditions. Upregulated chemokine gene expressions including Ccl5 and Cxcl10 were concurrent with increased numbers of T cells and monocytes, especially Ly6Clo monocytes in the CNS. Upregulation of Axl, Clec7a, Itgax, Ccl5, and Cxcl10 was also observed in NZB/NZW mice, indicating common lupus pathology. The primed status of microglia in FcγRIIB−/−Yaa mice was also demonstrated by morphological changes such as enlarged cell bodies with hypertrophic processes, and hyperreactivity to lipopolysaccharide. Immunohistochemistry of FcγRIIB−/−Yaa mice indicated reactive responses of astrocytes and vascular endothelium. Behavioral studies of FcγRIIB−/−Yaa mice revealed depressive-like behavior and heat hyperalgesia in the forced swim test and the tail-flick test, respectively. Our data indicated that microglia in lupus exhibit a unique primed phenotype characterized by the upregulated expressions of neurodegeneration-related genes and IFN-responsive genes. Interaction with peripheral cells and brain resident cells was presumed to orchestrate neuroinflammation. Targeting innate immune cells, such as microglia and monocytes, may be a promising therapeutic approach for neuropsychiatric SLE.

中文翻译：

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易患狼疮小鼠的全身自身免疫条件下小胶质细胞的独特致敏状态

系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是产生各种自身抗体。即使在中枢神经系统（CNS）中没有明显炎症的情况下，这种疾病也会导致神经精神疾病症状的丧失，但是涉及的机制仍然未知。作为神经精神疾病的致病机制，先天性免疫介导的炎症引起了人们的注意。我们研究了倾向于天然免疫的易患狼疮小鼠的中枢神经系统。使用三株狼疮易感小鼠FcγRIIB-/-Yaa，NZB和NZW（NZB / NZW）小鼠的F1杂种和MRL / Faslpr（MRL / lpr）小鼠来分析CNS免疫病理学。流式细胞仪分析表明，狼疮易感小鼠的脑CD45 +细胞数量比对照组增加。在易患狼疮的小鼠的小胶质细胞和CD11b +髓样细胞中观察到MHC I类和PDCA1上调，表明它们在对干扰素（IFN）的反应中被激活。FcγRIIB-/-Yaa小鼠的小胶质细胞基因表达分析揭示了IFN反应基因和炎症相关基因（包括Axl，Clec7a和Itgax）的上调，这些基因先前曾在神经退行性疾病和引发条件下报道过。包括Ccl5和Cxcl10在内的趋化因子基因表达上调与中枢神经系统中T细胞和单核细胞，尤其是Ly6Clo单核细胞数量的增加同时发生。在NZB / NZW小鼠中也观察到Axl，Clec7a，Itgax，Ccl5和Cxcl10的上调，表明常见的狼疮病理。FcγRIIB-/-Yaa小鼠中的小胶质细胞的启动状态还通过形态变化来证明，例如细胞肥大而肥大，对脂多糖的反应性也很高。FcγRIIB-/-Yaa小鼠的免疫组织化学表明星形胶质细胞和血管内皮的反应性反应。FcγRIIB-/-Yaa小鼠的行为研究显示，在强迫游泳试验和甩尾试验中分别表现出抑郁样行为和热痛觉过敏。我们的数据表明狼疮中的小胶质细胞表现出独特的引发表型，其特征在于神经变性相关基因和IFN反应基因的表达上调。据推测与周围细胞和大脑驻留细胞的相互作用可以协调神经炎症。针对先天免疫细胞，例如小胶质细胞和单核细胞，