Mechanistic study of celastrol-mediated inhibition of proinflammatory activation of macrophages in IgA nephropathy via down-regulating ECM1.

Increasing evidence suggests that the mononuclear/macrophage system is vital in amplifying the inflammatory cascade in IgA Nephropathy (IgAN). However, the pathogenic mechanism of macrophages in IgAN and targeted treatment strategies still need to be explored. This study found that botanical triterpene celastrol (CLT) effectively alleviated renal lesions, M1-like macrophage infiltration, inflammatory factors production, and improved renal function in IgAN mice. We found that the renal macrophages of IgAN patients had high expression of ECM1, a crucial molecule involved in macrophage inflammatory polarization, positively correlated with the IgAN clinical severity. In murine macrophage Raw 264.7 cells, CLT inhibited macrophage M1-like polarization and the output of TNF-α and IL-6 by downregulating the ECM1/STAT5 pathway. Mechanistically, molecular docking, CESTA, and immunoprecipitation verified that CLT directly bound to ECM1 and increased the ubiquitination of ECM1. Collectively, these results illustrated that CLT inhibited proinflammatory macrophage in IgAN by directly targeting ECM1 to promote ubiquitination degradation of ECM1. Therefore, this study may provide a theoretical basis for exploring the pathogenesis of IgAN and identifying new perspectives for targeted therapy of IgAN.