[Streptococcus salivarius-derived extracellular vesicles exacerbate progression of lupus nephritis by activating...

To investigate the regulatory effects of Streptococcus salivarius-derived extracellular vesicles (SS-EVs) on natural killer (NK) cell activation and cytotoxic function and their role in progression of systemic lupus erythematosus (SLE).

Peripheral blood and fecal samples were collected from 35 SLE patients and 38 healthy individuals to assess the number and proportion of peripheral T cells, B cells, and NK cells. Fecal DNA was extracted for PCR amplification of S. salivarius DNA fragments and quantitative analysis using agarose gel electrophoresis. SS-EVs isolated by ultracentrifugation and characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting were co-cultured with NK cells, whose activation status and cytotoxicity were evaluated in vitro using qPCR and flow cytometry. Twenty-four MRL/lpr mice were randomized into 3 groups (n=8) for treatment with gavage of 100 μL PBS or 20 μg E. coli-EVs or SS-EVs in 100 μL PBS. Kidney pathology, immune complex deposition, and peripheral cytokine levels were assessed with HE staining, immunofluorescence staining, and ELISA.

The number and proportion of peripheral NK cells were significantly reduced (P<0.0001) and the fecal abundance of S. salivarius was markedly increased in positive correlation with SLEDAI scores (R²=0.8369) in SLE patients. In vitro studies showed that SS-EVs significantly upregulated NK cell-activating receptors and enhanced NK-mediated cytotoxicity. In MRL/lpr mice, SS-EV treatment markedly exacerbated renal inflammation, promoted C3 and IgG immune complex deposition, and significantly increased serum levels of IL-6, TNF-α, IL-8, and CCL20.

S. salivarius is enriched in the gut of SLE patients and promotes NK-cell activation by releasing SS-EVs, which induce renal inflammation and immune complex deposition and contributes to SLE progression. S. salivarius and its EVs may represent novel therapeutic targets for treatment of SLE.