DNase I alleviates renal inflammatory injury in MRL/lpr mice by inhibiting NETs formation

Neutrophil extracellular traps (NETs) formation has been closely associated with renal inflammatory injury. We administered DNase I to MRL/lpr mice, monitored signs and renal pathology, quantified gene expression levels, and conducted flow cytometry and RNA-seq analysis. Following DNase I treatment, the lupus-related manifestations, renal pathology, and renal function were significantly improved in the LN mouse model. The expression levels of MPO and CitH3 were reduced, and the expression of inflammatory damage molecules, including IL-1ß, TNF-a, and Kim1, was down-regulated. RNA-seq analysis revealed that the neutrophil and T cell activation and chemotaxis pathways were suppressed, and the infiltration of cytotoxic immune cells in the kidneys was decreased in the DNase I-treated group compared to MRL/lpr mice. In conclusion, DNase I alleviates renal inflammatory injury by inhibiting the NETs/TLR4/MYD88 cell signaling axis, reducing the formation of NETs and the infiltration of immune inflammatory cells such as T cells and macrophages. These findings may provide a novel clinical prevention and treatment strategy for LN. Overall design: To further investigate the potential molecular mechanisms underlying DNase I-targeted NETs in the treatment of LN in a mouse model, we conducted RNA sequencing on kidney tissues from four 21-week-old MRL/lpr mice (Lpr), four MRL/lpr mice treated with DNase I (DNase), and three sex- and age-matched healthy control mice (Ctr).