The gene silencing of IRF5 and BLYSS effectively modulates the outcome of experimental lupus nephritis

Abstract

Systemic lupus erythematosus is a highly complex and hetero- geneous autoimmune disease mostly mediated by B cells. It is characterized by circulating self-reactive antibodies that depo- sit and form immune complexes in kidney, leading to irrepa- rable tissue damage and resulting in lupus nephritis. In a New Zealand Black X New Zealand White F1 mouse model, we tested two different small interfering RNA (siRNA) silencing treatments against interferon regulatory factor 5 (IRF5) and B cell-activating factor (BLYSS) expression and their combination in a second set of animals. The administra- tion of these two siRNAs separately prevented the progression of proteinuria and albuminuria at similar levels to that in cyclo- phosphamide animals. These treatments effectively resulted in a reduction of serum anti-double-stranded DNA (dsDNA) an- tibodies and histopathological renal score compared with non- treated group. Treated groups showed macrophage, T cell, and B cell infiltrate reduction in renal tissue. Moreover, kidney gene expression analysis revealed that siRNA treatments modulated very few pathways in contrast to cyclophosphamide, despite showing similar therapeutic effects. Additionally, the com- bined therapy tested in a second set of animals, in which the disease appeared more virulent, exhibited better results than monotherapies in the disease progression, delaying the disease onset and ameliorating the disease outcome. Herein, we pro- vide the potential therapeutic effect of both selective IRF5 and BLYSS silencing as an effective and potential treatment, particularly in early phases of the disease.