TMEM11-Dependent Cristae Architecture Restrains Imiquimod-Induced NLRP3 Inflammasome Activation via Mitochondrial ROS

Abstract

Imiquimod (IMQ) is a clinically approved drug widely used to treat skin malignancies; however, its application frequently provokes severe inflammation through NLRP3 inflammasome activation. The mechanism underlying IMQ-induced activation of the NLRP3 inflammasome is not completely defined. While IMQ-induced inhibition of mitochondrial electron transport chain complex I is necessary for activation of the NLRP3 inflammasome, it is not sufficient; suggesting presence of additional targets/triggers. The role of mitochondrial reactive oxygen species (mtROS) as the additional trigger to activate the inflammasome remains contentious based on conflicting reports. Using a unique genetic model lacking expression of mitochondrial membrane protein TMEM11 we reaffirm the role of mtROS in IMQ-induced NLRP3 inflammasome activation. Macrophages deficient in Tmem11, a mitochondrial contact site and cristae organizing system (MICOS)-associated membrane-protein, exhibit ultrastructural defects in cristae morphology without altering mitochondrial mass or mtDNA copy number. Loss of TMEM11 influences cristae length and density, reducing mitochondrial oxygen consumption. Tmem11-deficient macrophages exhibit normal NLRP3 inflammasome activation in response to canonical agonists (e.g., ATP, nigericin) but show caspase-1 hyperactivation and exaggerated IL-1{beta} and IL-18 secretion upon IMQ treatment. This exaggerated response is rescued by antioxidant treatment, confirming the role for mtROS. These findings demonstrate that cristae architecture restrains drug-induced mtROS to limit NLRP3 activation and that mtROS is a primary driver of IMQ-mediated NLRP3 inflammasome activation.