M2-ApoBDs as a therapeutic strategy for systemic lupus erythematosus: targeted macrophage reprogramming and treg differentiation.

Abstract

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.