The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages

Figure 6

Role of the LGM2605 in preventing asbestos-induced inflammation, oxidative/nitrosative cell damage, cell injury, and cell death proposed mechanism of asbestos-induced inflammation and oxidative/nitrosative stress and the protective effect of LGM2605. Asbestos exposure leads to the production of ROS (such as H₂O₂, ^.OH) that activates an inflammatory cascade, of which the NLRP3 inflammasome is involved. NLRP3 activation leads to the release of cytokines IL-1β and IL-18. These cytokines drive inflammation-induced cell death. Under these conditions, the damage-associated molecular pattern protein HMGB1 is either released by dead cells or passively secreted from inflamed cells. HMGB1 release can also lead to a feed forward cycle of IL-1β and IL-18 induction and activation. Importantly, asbestos-induced inflammation is largely driven by HMGB1 and the NLRP3 inflammasome. Frustrated phagocytosis of asbestos fibers may lead to cell necrosis and the subsequent release of HMGB1, which promotes the activation of the NLRP3 inflammasome. Asbestos-induced ROS generation exacerbates this signaling cascade and further promotes malignant transformation. Combined, HMGB1 and NLRP3 inflammasome activation, induces a proinflammatory signaling cascade that ultimately leads to IL-1β and TNFα secretion and NF-κB activation. LGM2605 exhibits a pluripotent role in preventing ROS/RNS generation and inflammation following asbestos exposure through several mechanisms: (1) LGM2605 directly scavenges free radicals (ROS, such as H₂O₂, ^.OH) and mitigates asbestos-induced ROS/RNS generation, (2) LGM2605 inhibits the proinflammatory NF-κB pathway presumably via reduced levels of ROS (either due to direct scavenging or due to increased antioxidant enzyme expression) or via direct inhibition of the transcription factor. LGM2605 decreased the levels of NLRP3 inflammasome (protein), HMGB1 (protein and mRNA), and the levels of iNOS (protein and mRNA), and (3) LGM2605 activates Nrf2 and induces the expression of cellular antioxidant and detoxification enzymes.