K⁺ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria

Groß CJ et al. Immunity 45, 761–773, 2016

Speaker: Fu-Yu Chan (詹復宇)                            Time: 15:10~16:00, Apr12, 2017

Commentator: Dr. Pin Ling (凌斌 老師)             Place: Room 601

Abstract:

Toll-like receptor (TLR)7 agonist imiquimod is a topical immune response modifier and is effective for the treatment of non-melanoma skin cancers.^[1] Imiquimod has TLR7-independent activities that are mechanistically unexplained, including NLRP3 inflammasome activation in myeloid cells and apoptosis induction in cancer cells. In this study, the authors investigated the mechanism of NLRP3 activation by imiquimod.^[2] NLRP3 activation by imiquimod did not require K⁺ efflux, but was dependent on reactive oxygen species (ROS). Imiquimod and the related molecule CL097 inhibited the quinone oxidoreductases NQO2 and mitochondrial Complex I. This induced a burst of ROS and thiol oxidation, and led to NLRP3 activation through NEK7, a recently identified component of this inflammasome. Metabolic consequences of Complex I inhibition and endolysosomaleffects of imiquimod might also contribute to NLRP3 activation. Furthermore, Imiquimod-induced NLRP3 activation was inhibited by MCC950, a small molecule capable of inhibiting NLRP3 activation by activators. Taken together, imiquimod and CL097 engage a ROS- and Complex I-driven, MCC950-sensitive, NEK7-dependent pathway for NLRP3 activation that is independent of K⁺ efflux.

References:

1.         Allam R et al. (2014). Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep. 15, 982–990.

2.         Schön M et al. (2003). Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J. Natl. Cancer Inst. 95, 1138–1149.