Kwun Audrey, Sullivan James K, Shelestak John, Merritt Kayla M, Liu Selena S, Mey Gabrielle, DeSilva Tara, Jørgensen Trine N
Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.
Brain Behav Immun. 2025 Aug;128:352-361. doi: 10.1016/j.bbi.2025.04.017. Epub 2025 Apr 15.
To investigate the role of Toll-like Receptor 7 (TLR7) in the development of neuropsychiatric lupus (NPSLE) in the B6.Nba2 murine model of SLE.
TLR7-deficient B6.Nba2 mice were evaluated for the development of NPSLE symptoms through behavioral testing with comparison groups of wild-type NPSLE-prone B6.Nba2 and B6 controls. Behavioral testing results were evaluated in the context of biomarker data, including flow cytometry for immune cell activation, and enzyme-linked immunosorbent assays (ELISA) to measure serum cytokine and autoantibody levels, including autoantibodies against double stranded DNA (dsDNA) and DWEYS peptide. Brain and spleen tissues waere harvested, and immuno histochemical studies and inflammatory gene activation obtained via qPCR were further analyzed to characterize immune system activation and SLE and NPSLE development in the mice.
TLR7-deficient mice exhibited reduced signs of systemic SLE, including decreased splenomegaly, anti-dsDNA titers, and immune cell activation compared to wild-type mice. However, TLR7-deficient mice displayed a similar behavioral pattern to the NPSLE-prone B6.Nba2 mice, indicating NPSLE development was not influenced by TLR7. Knockout of TLR7 in B6.Nba2 mice also led to increased expression of TLR4 and TLR9, which suggests a possible role for these receptors in NPSLE pathogenesis.
While systemic lupus-like disease in the B6.Nba2 mouse model is dependent on TLR7, NPSLE development is not and may be influenced by TLR4 and TLR9 signaling. Thus, there may be separate mechanisms driving peripheral SLE compared to NPSLE with possible implications for pharmacologic management.
在SLE的B6.Nba2小鼠模型中研究Toll样受体7（TLR7）在神经精神性狼疮（NPSLE）发病过程中的作用。
通过行为测试评估TLR7缺陷型B6.Nba2小鼠NPSLE症状的发展情况，并与野生型NPSLE易感B6.Nba2和B6对照分组进行比较。行为测试结果结合生物标志物数据进行评估，包括用于免疫细胞激活的流式细胞术，以及用于测量血清细胞因子和自身抗体水平（包括抗双链DNA（dsDNA）和DWEYS肽自身抗体）的酶联免疫吸附测定（ELISA）。采集脑和脾组织，进一步分析免疫组织化学研究结果以及通过qPCR获得的炎症基因激活情况，以表征小鼠免疫系统激活以及SLE和NPSLE的发展。
与野生型小鼠相比，TLR7缺陷型小鼠表现出系统性SLE体征减轻，包括脾肿大减小、抗dsDNA滴度降低和免疫细胞激活减少。然而，TLR7缺陷型小鼠表现出与NPSLE易感B6.Nba2小鼠相似的行为模式，表明NPSLE的发展不受TLR7影响。在B6.Nba2小鼠中敲除TLR7还导致TLR4和TLR9表达增加，这表明这些受体可能在NPSLE发病机制中发挥作用。
虽然B6.Nba2小鼠模型中的系统性狼疮样疾病依赖于TLR7，但NPSLE的发展并非如此，且可能受TLR4和TLR9信号传导影响。因此，与NPSLE相比，驱动外周SLE的机制可能不同，这可能对药物治疗有影响。
