Systemic lupus erythematosus (SLE) is a chronic, progressive autoimmune disorder characterized by aberrant activation of T and B lymphocytes and inflammation of small blood vessels, leading to multisystem involvement. The kidneys are among the primary organs affected, with lupus nephritis manifesting as vascular inflammation and injury, tubular degeneration and necrosis, immune complex deposition, and immune cell infiltration. These pathological changes impair critical renal functions, including blood filtration, elimination of metabolic waste, and maintenance of systemic homeostasis, making lupus nephritis one of the leading causes of mortality in SLE patients. Exosomes are extracellular vesicles ranging from 30 to 200 nm in diameter that can be secreted by various cell types. They carry proteins, nucleic acids, and other biomolecules reflective of the physiological or pathological state of their parent cells, serving as key mediators of intercellular communication. Emerging evidence indicates that exosomes play a significant role in the pathogenesis and progression of SLE and may serve as potential biomarkers for disease monitoring. Exosomes derived from multiple cell sources have been implicated in the development of lupus nephritis. This study aims to investigate the composition and mechanistic roles of plasma-derived exosomes from SLE patients in inducing vascular endothelial cell (VEC) dysfunction and exacerbating renal inflammation.

Plasma exosomes were isolated from patients with SLE and healthy controls, followed by administration to MRL/lpr lupus mice and zebrafish embryos, respectively. The effects on vascular inflammation and endothelial barrier integrity were systematically evaluated. Subsequently, the functional impact of SLE-derived plasma exosomes on human umbilical vein endothelial cells (HUVECs) was validated in vitro. A three-dimensional (3D) human vascular organoid model was then established and co-cultured with plasma exosomes from SLE patients to further assess their effect on vascular barrier integrity. Differentially expressed proteins were identified through proteomic profiling of exosomes isolated from SLE patients and healthy individuals. The role and underlying mechanism of the differentially expressed protein ICOSLG in vascular endothelial cells (VECs) were investigated using Western blotting, immunofluorescence staining, and co-culture assays. The therapeutic potential of recombinant ICOSLG protein and its antagonist ICOS was evaluated in MRL/lpr lupus mice with nephritis. Finally, the correlation between circulating ICOSLG levels and clinical parameters in SLE patients was analyzed using enzyme-linked immunosorbent assay (ELISA).

1. Plasma exosomes from SLE patients significantly exacerbated inflammatory infiltration and tissue damage in MRL/lpr mice and markedly reduced the expression of ZO-1 colocalized with VECs in renal tissues. Confocal microscopy revealed evident tracer leakage in the dorsal aortae of zebrafish embryos exposed to SLE-derived exosomes, indicating impaired vascular integrity. 2. In vitro, SLE-derived exosomes induced functional alterations in HUVECs, including decreased cell viability and disrupted intercellular tight junctions. 3. Tight junction dysfunction was similarly observed in vascular organoids treated with SLE patient-derived exosomes. 4. Proteomic analysis demonstrated that plasma exosomes from SLE patients exhibited upregulated expression of many proteins compared to those from healthy individuals. Western blot analysis confirmed significant elevation of vWF and ICOSLG in SLE-derived exosomes. 6. Pre-stimulated VECs with ICOSLG significantly activated peripheral blood T cells from SLE patients, promoting the secretion of pro-inflammatory cytokines such as IFN-γ, IL-4, IL-17 and IL-6. Furthermore, VEC dysfunction—manifested as reduced tube formation and migration—was exacerbated in these co-culture systems. 7. Compared with the IgG isotype control group, MRL/lpr mice treated with recombinant ICOSLG exhibited pronounced renal inflammatory infiltration, downregulation of ZO-1 in VECs, and increased splenic infiltration of Th1, Th17 and Tfh cells. Conversely, administration of anti-ICOS antibody ameliorated renal inflammation and VEC injury in treated mice. 8. Serum soluble ICOSLG levels in SLE patients were significantly higher than those in healthy controls and positively correlated with SLEDAI scores and anti-dsDNA antibody titers.

Plasma exosomes derived from SLE patients impair tight junctions in vascular endothelial cells and compromise vascular barrier integrity. ICOSLG is a key mediator responsible for VEC dysfunction induced by SLE-derived exosomes. Dysfunctional VECs pre-exposed to ICOSLG further exacerbate vascular injury through aberrant activation of T cells. Blocking the ICOSLG–ICOS pathway in vivo has been shown to alleviate lupus nephritis, and the concentration of ICOSLG is significantly correlated with clinical disease indicators in patients. Therefore, ICOSLG represents a promising therapeutic target for the prevention and treatment of systemic lupus erythematosus.