Circulating plasma derived exosomes from systemic lupus erythematosus aggravate lupus nephritis through miR-122-5p/FOXO3-mediated macrophage activation

Abstract

Abstract Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disease characterized by dysregulation in both innate and adaptive immunity. Polarization of macrophages into M1/M2 macrophages affects the development of lupus. Exosomes-miRNA plays a crucial role in disease progression. This study aims to explore the mechanism of circulating exosomes participating in the pathogenesis of SLE and seek new therapeutic targets. Plasma derived-exosomes from SLE patients accelerated the disease progression and polarization of macrophages of the kidney in MRL/lpr mice. Exosomes were taken up by macrophages and stimulated macrophage polarization in vitro. MiRNA-sequence analysis revealed that plasma-derived exosomal miR-151a-5p, miR-1180a-5p, miR-1246 and miR-122-5p were abnormal. Of them, the expression of miR-122-5p was significantly upregulated in SLE exosomes, and positively correlated with systemic lupus erythematosus disease activity index (SLEDAI) and the dsDNA levels. Compared with SLE exosomes, inhibition of circulating exosomal miR-122-5p from SLE patients relieved lupus clinical aspects and polarization of macrophage. SLE exosomal miR-122-5p motivated M1 macrophage polarization by targeting FOXO3/NF-κB signaling pathway. Based on these findings, we conclude that SLE exosomal miR-122-5p can promote M1 macrophage polarization via targeting FOXO3/NF-κB signaling pathway and participate in pathogenesis of SLE. Collectively, plasma-derived exosomal miR-122-5p is a promising and effective target for treating SLE. Graphical Abstract

Keywords

• Systemic lupus erythematosus
• Exosomes
• miR-122-5p
• Macrophages