Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States; Division of Medical Sciences, Harvard Medical School, Boston, MA, United States.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.
Brain Behav Immun. 2023 Nov;114:511-522. doi: 10.1016/j.bbi.2023.06.021. Epub 2023 Jun 25.
Among systemic lupus erythematosus (SLE) patients, neuropsychiatric symptoms are highly prevalent, being observed in up to 80% of adult and 95% of pediatric patients. Type 1 interferons, particularly interferon alpha (IFNα), have been implicated in the pathogenesis of SLE and its associated neuropsychiatric symptoms (NPSLE). However, it remains unclear how type 1 interferon signaling in the central nervous system (CNS) might result in neuropsychiatric sequelae. In this study, we validate an NPSLE mouse model and find an elevated peripheral type 1 interferon signature alongside clinically relevant NPSLE symptoms such as anxiety and fatigue. Unbiased single-nucleus sequencing of the hindbrain and hippocampus revealed that interferon-stimulated genes (ISGs) were among the most highly upregulated genes in both regions and that gene pathways involved in cellular interaction and neuronal development were generally repressed among astrocytes, oligodendrocytes, and neurons. Using image-based spatial transcriptomics, we found that the type 1 interferon signature is enriched as spatially distinct patches within the brain parenchyma of these mice. Our results suggest that type 1 interferon in the CNS may play an important mechanistic role in mediating NPSLE behavioral phenotypes by repressing general cellular communication pathways, and that type 1 interferon signaling modulators are a potential therapeutic option for NPSLE.
在系统性红斑狼疮 (SLE) 患者中，神经精神症状高度普遍，高达 80%的成年患者和 95%的儿科患者存在此类症状。1 型干扰素，尤其是干扰素-α（IFNα），被认为与 SLE 及其相关的神经精神症状（NPSLE）的发病机制有关。然而，中枢神经系统（CNS）中 1 型干扰素信号如何导致神经精神后遗症仍不清楚。在这项研究中，我们验证了一个 NPSLE 小鼠模型，并发现外周 1 型干扰素特征升高，同时伴有临床相关的 NPSLE 症状，如焦虑和疲劳。对后脑和海马体的无偏单细胞核测序表明，干扰素刺激基因（ISGs）在这两个区域中是上调最明显的基因之一，并且细胞间相互作用和神经元发育相关的基因途径在星形胶质细胞、少突胶质细胞和神经元中普遍受到抑制。通过基于图像的空间转录组学，我们发现 1 型干扰素特征在这些小鼠大脑实质中作为空间上不同的斑块富集。我们的结果表明，CNS 中的 1 型干扰素可能通过抑制一般细胞通讯途径在介导 NPSLE 行为表型方面发挥重要的机制作用，并且 1 型干扰素信号调节剂是治疗 NPSLE 的潜在选择。
