Targeting MLKL ameliorates T-2 toxin-induced cartilage damage by inhibiting chondrocyte death and matrix degradation in mice

Abstract

T-2 toxin is the most toxic mycotoxin found in contaminated food and animal feed that threatens health. Exposure to T-2 toxin causes cartilage damage and leads to joint disorders, but the mechanisms underlying T-2 toxin-induced cartilage damage remain unclear. The results showed that T-2 toxin-induced chondrocyte death in articular cartilage from rats fed T-2 toxin (200 ng/g b.w./day) caused a significant increase in phosphorylated receptor-interacting protein 3 (p-RIPK3) and phosphorylated mixed lineage kinase-like protein (p-MLKL). In vitro studies showed that T-2 toxin (48 ng/mL) reduced the viability of C-28/I2 chondrocytes, increased cell apoptosis, and significantly upregulated the expression of p-MLKL. The results suggest that chondrocyte necroptosis is involved in T-2 toxin-induced cartilage damage. Furthermore, necrostatin-1 (Nec-1), a necroptosis inhibitor, significantly attenuated T-2 toxin-induced cell death and the increase of p-MLKL. Further studies showed that mlkl^−/− mice suppressed T-2 toxin-induced chondrocyte death, and mlkl^−/− mice upregulated T-2 toxin-induced proteoglycan content and type II collagen reduction in mouse articular cartilage, and reduced increased matrix metalloproteinase-13 expression. Besides, the p-RIPK3 and p-MLKL were significantly increased in the articular cartilage of KBD patients. This study highlights the role of RIPK3/MLKL-mediated necroptosis in T-2 toxin-induced articular cartilage damage. Inhibition of MLKL alleviates T-2 toxin-induced cartilage damage by reducing chondrocyte death and matrix degradation in mice. These results suggest a potential therapeutic target for mitigating T-2 toxin-induced cartilage damage.