美国范斯坦医学研究所Betty Diamond团队在研究中取得进展。他们发现红斑狼疮自身抗体通过持续的HMGB1:RAGE信号传导引发神经炎症，并通过增加LAIR-1的表达逆转神经炎症。这一研究成果发表在2024年3月6日出版的国际学术期刊《自然-免疫学》上。

在本研究中，研究人员建立了一种红斑狼疮样认知障碍模型，当与兴奋性神经元受体发生交叉反应的抗体穿透海马体时，会导致海马体神经元立即发生自限性兴奋毒性死亡，随后存活的神经元树突复杂性会显著丧失。这种损伤造成的不平衡在小鼠体内至少持续一年。

研究发现了小胶质细胞激活和小胶质细胞依赖性突触消除的前反馈循环，这取决于神经元分泌的高迁移率组盒1蛋白（HMGB1），HMGB1与高级糖化终产物受体（RAGE）结合，导致小胶质细胞分泌C1q、白细胞介素-10的上调，从而导致白细胞相关免疫球蛋白样受体1（LAIR-1）（C1q的抑制受体）下调。使用中枢作用的血管收缩素转换酶抑制剂，或血管收缩素受体阻断剂治疗后，可恢复平衡、小胶质细胞静止和完整的空间记忆。

研究人员表示，认知障碍是神经系统性红斑狼疮的一种常见表现，多达80%的患者会出现认知障碍，并导致生活质量下降。

附：英文原文

Title: Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression

Author: Carroll, Kaitlin R., Mizrachi, Mark, Simmons, Sean, Toz, Bahtiyar, Kowal, Czeslawa, Wingard, Jeffrey, Tehrani, Nazila, Zarfeshani, Aida, Kello, Nina, El Khoury, Lara, Weissman-Tsukamoto, Rachel, Levin, Joshua Z., Volpe, Bruce T., Diamond, Betty

Issue&Volume: 2024-03-06

Abstract: Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.

DOI: 10.1038/s41590-024-01772-6

Source: https://www.nature.com/articles/s41590-024-01772-6