Treatment with caspase-1 inhibitor diminishes kidney disease in MRL-Faslpr mice and delays systemic illness.

OBJECTIVES

To investigate the therapeutic potential of caspase-1 inhibition in systemic lupus erythematosus (SLE) and lupus nephritis (LN) using the MRL-Faslpr mouse model.

METHODS

Female Murphy Roths large (MRL)-Faslpr mice were treated with a caspase-1 inhibitor (pralnacase) or sham treatment from 2.5 to 5.5 months of age. Disease progression was assessed through analysis of systemic and renal parameters, including proteinuria, blood urea nitrogen, kidney histopathology and immune cell infiltration. Cytokine expression and caspase activity were measured to elucidate the mechanism of action. Additional experiments with interleukin (IL)-1 receptor antagonist and pancaspase inhibition treatment as well as post-disease onset intervention were conducted.

RESULTS

Caspase-1 inhibition significantly reduced systemic inflammation, lymphadenopathy and skin lesions in MRL-Faslpr mice. Treated mice exhibited decreased proteinuria, improved renal function and reduced kidney pathology. The treatment specifically targeted caspase-1 activity, leading to decreased IL-18 levels as well as attenuated immune cell activation and infiltration in the kidneys. Selective caspase-1 inhibition showed comparable results with pancaspase inhibition. IL-1 receptor antagonist treatment did not significantly affect disease progression, suggesting IL-18 as the primary driver of pathology. Post-disease onset intervention with caspase-1 inhibition also showed efficacy, although to a lesser extent than pre-onset treatment.

CONCLUSIONS

Caspase-1 inhibition effectively ameliorates both systemic and renal manifestations of SLE in MRL-Faslpr mice, primarily through suppression of IL-18-mediated inflammation. This study identifies caspase-1 as a promising therapeutic target for SLE and LN, warranting further investigation in clinical trials.