NLRP3 inflammasome in immune cells regulates metastatic potential of cancer

Abstract

Abstract One of the main features of tumor microenvironment is inflammation accompanied with the activation of immune cells and the production of pro-inflammatory cytokines. IL-1b, one of the critical cytokines released by immune cells to promote tumor growth and metastasis by acting on its receptor, IL-1R, and to culminate in the secondary activation of immune cells and the expression of immune cytokines. Inflammasome plays a critical role in production of mature IL-1b through activation of capspase-1. Therefore, we investigated whether regulation of NLRP3 inflammasome in macrophages affected the metastatic potential of tumor cells. Activation of NLRP3 inflammasome was induced by ATP in bone marrow-derived primary mouse macrophages. The metastatic potential of tumor cells was determined by transwell migration and invasion assays. Wild-type macrophages stimulated with ATP increased the migration and invasion of melanoma cells (B16F10). However, NLRP3- or caspase-1-knockout macrophages showed greatly decreased ability to promote the migration and invasion of melanoma cells. Treatment with celastrol, an inhibitor of NLRP3 inflammasome, blocked the ability of macrophages to stimulate migration and invasion of melanoma cells. The results show that inhibition of the NLRP3 inflammasome in macrophages by genetic deficiency or a pharmacological inhibitor leads to decrease of the metastatic potential of tumor cells. The results would provide a novel anti-cancer immuntherapy to regulate the activity of NLRP3 inflammasome in tumor microenvironment. [Supported by grants from BK21 PLUS program, NRF-2019R1A2C2085739, and NRF-2017R1A4A1015036].