Urine-Derived CD105-Positive Exosome Promotes Macrophage M1 Polarization Through the TGF-β1/Smad3 Signaling Axis To Exacerbate Lupus Nephritis.

This study investigated the regulatory role of exosomal CD105 in macrophage polarization and its mechanisms in lupus nephritis (LN). Analysis of samples from 20 LN patients revealed significant CD105 overexpression in kidney tissues and urinary exosomes. Exosomes were isolated from the urine specimens and tested for CD105 expression levels. Exosomes overexpressing or knocking down CD105 were co-cultured with macrophages to detect the levels of M1/M2 markers (CD86, IL-6, ARG-1, and IL-10) and changes in the TGF-β1/Smad3 pathway. Rescue experiments were performed using the TGF-β1 agonist (80116-RNAH) and inhibitor (SB431542). For in vivo experiments, exosomes overexpressing or knocking down CD105 were injected into a systemic lupus erythematosus model mice (MRL/lpr) to observe changes in renal inflammation and M1 macrophage infiltration. CD105 was significantly overexpressed in LN kidney tissues and urinary exosomes. CD105 overexpression in exosomes led to a decrease in p-Smad3 levels, up-regulation of M1 markers (CD86/IL-6), and down-regulation of M2 markers (ARG-1/IL-10); on the other hand, CD105 knockdown had the opposite effect in exocytosis. 80,116-RNAH reversed the effects of CD105-induced M1 polarization. In vivo experiments confirmed that CD105 overexpression in exosomes exacerbated renal inflammation and M1 macrophage infiltration, while CD105 knockdown in exosomes attenuated renal injury. Exosomal CD105 critically drives LN progression by inducing macrophage M1 polarization through inhibition of the TGF-β1/Smad3 signaling axis. Our findings provides a new direction for the study of LN pathogenesis and the development of therapeutic targets.