Lymph node-targeted cyclosporine A alleviates myocarditis in lupus mice by inhibiting CD68 + macrophage-driven lymphangiogenesis

Abstract

Lupus myocarditis, a severe and often underdiagnosed complication of systemic lupus erythematosus (SLE), remains challenging to treat due to the complex inflammatory processes involved. While lymphangiogenesis has been implicated in lupus nephritis, its role in myocarditis is not well understood. This study investigates the potential of lymph node-targeted cyclosporine A (CsA) as a therapeutic approach for lupus myocarditis. Using a lupus mouse model, we explored the effects of localized immunosuppression through polymer nanoparticles designed to deliver CsA with lymph node-targeting functionality (P2Ns-GA-CsA), CsA without targeting (P2Ns-CsA), and a commercial CsA formulation as controls. Our results demonstrate that P2Ns-GA-CsA significantly alleviates inflammation in lupus myocarditis, as evidenced by a reduction in macrophage infiltration (CD68 + cells) and lower levels of pro-inflammatory cytokines. Histological analysis revealed improvements in cardiac function and a decrease in myocardial fibrosis. Moreover, P2Ns-GA-CsA inhibited pathological lymphangiogenesis by downregulating VEGF-C and VEGFR3 expression, restoring lymphatic vessel density. Additionally, treatment enhanced PGC1α signaling, improving metabolic regulation and further suppressing inflammation. This study highlights the involvement of inflammation-driven lymphangiogenesis in lupus myocarditis and demonstrates that P2Ns-GA-CsA provides superior anti-inflammatory, cardioprotective, and anti-lymphangiogenic effects. These findings suggest that targeted immunosuppressive therapies could offer a promising strategy for managing cardiovascular complications in lupus.