Regulatory effect of cadmium on inflammasome activation and and its upstream mechanisms

Abstract

Objective: Cadmium (Cd), a major component of cigarette smoke, disrupts the immune functions of lung macrophage and can lead to development of chronic obstructive pulmonary disease (COPD). Although Cd are known to promote the production of pro-inflammatory cytokines, the regulatory effects of Cd on inflammasome signaling has not been fully explored.

Method: Inflammasome signaling was induced in two steps. First, macrophages were primed with LPS (1 μg/ml) for 3 h. Subsequently, the cells were treated with different combinations of three types of inflammasome triggers (NLRP3, NLRC4, and AIM2) and Cd (10 μM) for 1h. The inflammasome and its intracellular regulation were assessed by western blot, ASC pyroptosome formation, quantitative PCR, and mitochondrial dysfunction assays.

Result: We observed that although Cd attenuates activation of the NLRP3, NLRC4 and AIM2 inflammasome in macrophages as determined by caspase-1 processing and interleukin-1β production. In addition, Cd treatment inhibited Toll-like receptor (TLR)-dependent reduction of pro-inflammatory cytokines in macrophages. The mechanistic study revealed that Cd also suppressed the assembly of the NLRP3 inflammasome by decreasing ASC oligomerization and GSDMD cleavage, preventing pyroptosis. Furthermore, we found that Cd treatment enhanced reduction of mitochondrial ROS and pathological stress granule (SG) formation

Conclusion: Collectively, these findings demonstrate that Cd could impair inflammasome-mediated innate immune responses through mitochondrial dysfunction and may increase susceptibility to respiratory infection in the various pulmonary diseases.