Mesenchymal Stromal Cell Therapy Alleviates Lupus Nephritis Through Inhibiting Caspase‐4/5/11–Mediated Noncanonical Pyroptosis in Macrophages

OBJECTIVE: Caspase-4/5/11-mediated noncanonical pyroptosis emerges as a contributing factor in immune responses under pathologic conditions. However, its precise role in the development of lupus nephritis (LN) remains largely unknown. Although mesenchymal stromal cells (MSCs) have demonstrated promising therapeutic effects on LN, whether MSCs influence pyroptosis in macrophages remains unknown. This study aimed to elucidate the role of caspase-4/5/11-mediated noncanonical pyroptosis in macrophages during the pathogenesis of LN and explore the impact of MSCs on macrophages. METHODS: The expression level of noncanonical pyroptosis in macrophages was assessed in patients and mice with LN. Blood samples from 19 patients with refractory systemic lupus erythematosus receiving MSC transplantation (MSCT) were collected. Caspase-11 inhibitor wedelolactone and MSCs were administered to MRL/lpr mice to examine the therapeutic efficacy. MSCs were cocultured with macrophages from MRL/lpr mice to explore effects and related mechanisms. RESULTS: Noncanonical pyroptosis signaling was activated in macrophages and kidney tissues from humans and mice with LN. The expression level of caspase-4 was increased and positively correlated with the active index and chronic index in the kidneys of patients with LN. The end products of pyroptosis directly induced cell death and reduced functional markers expression in murine podocytes. The caspase-11 inhibitor effectively alleviated renal damage in lupus mice. MSCT significantly deactivated pyroptosis signaling both in patients and lupus-prone mice. Mechanically, galectin-3 and interleukin-10 (IL-10) are essential for MSCs to inhibit noncanonical pyroptosis of LN macrophages. CONCLUSION: Our findings showed that MSCT ameliorates LN by inhibiting the caspase-4/5/11-mediated pyroptosis in macrophages, possibly via secreting galectin-3 and IL-10.