Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) affect over one-half of SLE patients, yet underlying mechanisms remain largely unknown. We demonstrate that SLE-prone mice (CReCOM) develop NP-SLE, including behavioral deficits prior to systemic autoimmunity, reduced brain volumes, decreased vascular integrity, and brain-infiltrating leukocytes. NP-SLE microglia exhibit numerical expansion, increased synaptic uptake, and a more metabolically active phenotype. Microglia from multiple SLE-prone models express a “NP-SLE signature” unrelated to type I interferon. Rather, the signature is associated with lipid metabolism, scavenger receptor activity and downregulation of inflammatory and chemotaxis processes, suggesting a more regulatory, anti-inflammatory profile. NP-SLE microglia also express genes associated with disease-associated microglia (DAM), a subset of microglia thought to be instrumental in neurodegenerative diseases. Further, expression of “NP-SLE” and “DAM” signatures correlate with the severity of behavioral deficits in young SLE-prone mice prior to overt systemic disease. Our data are the first to demonstrate the predictive value of our newly identified microglia-specific “NP-SLE” and “DAM” signatures as a surrogate for NP-SLE clinical outcomes and suggests that microglia-intrinsic defects precede contributions from systemic SLE for neuropsychiatric manifestations.

系统性红斑狼疮（NP-SLE）的神经精神症状会影响超过一半的SLE患者，但其基本机制仍不清楚。我们证明，SLE易感小鼠（CReCOM）发展为NP-SLE，包括全身自身免疫之前的行为缺陷，脑容量减少，血管完整性下降和脑浸润白细胞。NP-SLE小胶质细胞显示出数值扩展，突触摄取增加和新陈代谢活跃的表型。来自多个SLE易感模型的小胶质细胞表达与I型干扰素无关的“ NP-SLE信号”。而是，该签名与脂质代谢，清道夫受体活性以及炎性和趋化性过程的下调相关，这表明更具调节性，抗炎性。NP-SLE小胶质细胞还表达与疾病相关的小胶质细胞（DAM）相关的基因，DAM是小胶质细胞的一个子集，被认为有助于神经退行性疾病。此外，“ NP-SLE”和“ DAM”签名的表达与明显的全身性疾病之前易患SLE的年轻小鼠的行为缺陷严重程度相关。我们的数据首次证明了我们新发现的小胶质细胞特异性“ NP-SLE”和“ DAM”签名作为NP-SLE临床结果的预测价值，并表明小胶质细胞固有缺陷先于系统性SLE对神经精神病学的贡献表现形式。“ NP-SLE”和“ DAM”标记的表达与明显的全身性疾病之前易患SLE的年轻小鼠行为缺陷的严重程度相关。我们的数据首次证明了我们新发现的小胶质细胞特异性“ NP-SLE”和“ DAM”签名作为NP-SLE临床结果的预测价值，并表明小胶质细胞固有缺陷先于系统性SLE对神经精神病学的贡献表现形式。“ NP-SLE”和“ DAM”标记的表达与明显的全身性疾病之前易患SLE的年轻小鼠行为缺陷的严重程度相关。我们的数据首次证明了我们新发现的小胶质细胞特异性“ NP-SLE”和“ DAM”签名作为NP-SLE临床结果的预测价值，并表明小胶质细胞固有缺陷先于系统性SLE对神经精神病学的贡献表现形式。