Elevated IL-15 levels in systemic lupus erythematosus: potential pathogenesis insight and therapeutic target

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by persistent immune cell activation and the overproduction of autoantibodies, affecting various organs such as joints, kidneys, and skin. Interleukin-15 (IL-15) is a pleiotropic cytokine that modulates immune cells of the innate and adaptive immune systems, playing a crucial role in the development of inflammatory and protective immune responses. However, the role of IL-15 in SLE pathogenesis and the therapeutic effects of IL-15 blockade on SLE remain unknown. In this study, we conducted flow cytometry analysis and identified a significant increase in the frequencies of IL-15⁺ and IL-15R⁺ cells in peripheral blood CD4⁺ T cells, CD8⁺ T cells, dendritic cells (DCs), monocytes, and natural killer (NK) cells of patients with SLE compared to healthy controls (HCs). Besides, we found elevated levels of serum IL-15 in SLE patients compared to HCs. Furthermore, we evaluted the effectiveness of IL-15 mAb treatment in a chronic graft-versus-host disease (cGVHD) mouse model of SLE. We observed that the IL-15 mAb treatment effectively reduced the frequencies of CD4⁺CD44^hiCD62L^loPD-1⁺CD153⁺ senescent CD4⁺ T cells, B220⁺CD11c⁺T-bet⁺ age-associated B cells (ABCs), Tfh cells, and germinal center (GC) B cells, alleviated lupus-associated manifestations such as serum anti-double-stranded DNA antibody (anti-dsDNA) and kidney injury in the SLE mouse model of cGVHD. These findings provide compelling preclinical evidence suggesting the pathogenic role of IL-15 in SLE and the therapeutic potential of IL-15 blockade in the treatment of SLE.