Ji Juan, Yang Shaoying, Xu Yongxin, He Qian, Liang Qian, Feng Guijuan, Xia Yunfei, Yang Mei, Huang Yuting, Yang Junling, Dong Chen, Zhao Rui, Wang Yunan, Guo Genkai, Sha Xiaoqi, Li Jing, Guo Yuehua, Gu Zhifeng
Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
J Nanobiotechnology. 2025 May 16;23(1):354. doi: 10.1186/s12951-025-03437-4.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects various organs and systems, significantly impacting patients' health and quality of life. Conventional drugs, including glucocorticoids and standard immunosuppressive drugs, may not be enough to achieve a satisfactory therapeutic outcome in some refractory SLE patients. The abnormal phenotype and function of macrophages participate in the development of SLE. The targeted delivery to reprogram macrophage in SLE has been a long-standing challenge. Apoptotic bodies (ApoBDs) are essential for intercellular communications. This study aims to explore an effective and targeted treatment to SLE via macrophage reprogramming and Treg differentiation. In this work, we found that M2 macrophages-derived ApoBDs (M2-ApoBDs) could selectively target and localize to the spleen, where they were engulfed by splenic macrophages (phagocytic rate 73.4%). Single-cell RNA sequencing revealed that the efferocytosis of M2-ApoBDs triggered transcriptional changes in M2 (anti-inflammatory) macrophages within the spleen, subsequently promoting the differentiation of Treg cells in vivo. Immunological experiments revealed that M2-ApoBDs prompted the reprogramming of M2 macrophages in vitro, which subsequently influenced Treg cell differentiation via ligand-receptor interactions. In SLE mice, M2-ApoBDs alleviated the disease progression, including 24-hours urinary protein, plasma creatinine, plasma C3 levels, and glomerular sclerosis and interstitial fibrosis. These findings show that M2-ApoBDs can targeted-modulate macrophage polarization and Treg immune regulation, offering a novel therapeutic strategy for the effective treatment of SLE.
系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，会影响多个器官和系统，对患者的健康和生活质量产生重大影响。包括糖皮质激素和标准免疫抑制药物在内的传统药物，在一些难治性SLE患者中可能不足以取得令人满意的治疗效果。巨噬细胞的异常表型和功能参与了SLE的发展。在SLE中靶向递送以重编程巨噬细胞一直是一项长期挑战。凋亡小体（ApoBDs）对于细胞间通讯至关重要。本研究旨在探索一种通过巨噬细胞重编程和调节性T细胞（Treg）分化来有效且靶向治疗SLE的方法。在这项工作中，我们发现M2巨噬细胞衍生的凋亡小体（M2-ApoBDs）可以选择性地靶向并定位于脾脏，在那里它们被脾巨噬细胞吞噬（吞噬率为73.4%）。单细胞RNA测序显示，M2-ApoBDs的胞葬作用触发了脾脏内M2（抗炎）巨噬细胞的转录变化，随后在体内促进了Treg细胞的分化。免疫学实验表明，M2-ApoBDs在体外促使M2巨噬细胞重编程，随后通过配体-受体相互作用影响Treg细胞分化。在SLE小鼠中，M2-ApoBDs减轻了疾病进展，包括24小时尿蛋白、血浆肌酐、血浆C3水平以及肾小球硬化和间质纤维化。这些发现表明，M2-ApoBDs可以靶向调节巨噬细胞极化和Treg免疫调节，为有效治疗SLE提供了一种新的治疗策略。
