Targeting RIPK1 is a promising therapeutic avenue for systemic lupus erythematosus.

BACKGROUND

Necroptosis plays a significant role in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Nonetheless, the therapeutic potential of necroptosis inhibition in these conditions remains unclear.

METHODS

This study examines the systemic therapeutic effects of Necrostatin-1 (Nec-1), an inhibitor of receptor-interacting serine/threonine kinase 1 (RIPK1), in MRL/lpr lupus-prone mice.

RESULTS

Immunohistochemical analysis in renal tissue of active LN patients and MRL/lpr mice demonstrated elevated levels of pRIPK1 and pMLKL. A 28-day treatment with Nec-1 significantly ameliorated the histological manifestations of SLE, including alopecia, skin erythema, arthritis, and nephritis, in MRL/lpr mice. Notably, it mitigated acute lesion features such as LN perivascular inflammation and reduced the presence of pRIPK1 and pMLKL positive immune cells in the kidney. Mechanistically, Nec-1 treatment may exert its therapeutic effects on SLE by decreasing the proportion of Th17 cells in MRL/lpr mice.

CONCLUSION

These findings suggest that targeting RIPK1 hold promise as a therapeutic strategy for the management of SLE. Key Points • Necroptosis markers are upregulated in renal immune cells of active LN patients and MRL/lpr mice. • Necrostatin-1 (Nec-1) ameliorates clinical, serological, and histological features in MRL/lpr mice. • Nec-1 exerts its therapeutic effect by inhibiting necroptosis in immune cells, which subsequently reduces Th17 cell frequency and IL-17A levels.