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

Imiquimod (IMQ) is a drug commonly used to treat skin cancers, but it can cause excessive inflammation by activating the NLRP3 inflammasome. Scientists are still trying to understand exactly how IMQ triggers this activation. While they know that IMQ inhibits the electron transport chain complex I in mitochondria, which is necessary for NLRP3 activation, other factors are also involved. Some studies suggest that mitochondrial reactive oxygen species (mtROS) may play a role in this process, but the evidence has been mixed.

To investigate this further, researchers used a special genetic model of macrophages that lacked the TMEM11 protein. TMEM11 is a component of the mitochondrial contact site and cristae organizing system (MICOS), which helps shape the structure of mitochondria. The researchers found that macrophages missing TMEM11 showed unusual cristae shapes, with shorter and denser cristae, and reduced ability to consume oxygen. This affected the production of mtROS.

Interestingly, macrophages lacking TMEM11 still activated the NLRP3 inflammasome in response to other triggers, like ATP or nigericin. However, when these TMEM11-deficient cells were exposed to IMQ, they showed an exaggerated activation of the inflammasome, producing higher levels of the inflammatory cytokines IL-1β and IL-18. This abnormal response could be stopped by using an antioxidant, which confirmed the importance of mtROS.

The findings demonstrate that the shape and organization of the mitochondria, specifically the cristae architecture, play a crucial role in controlling the production of mtROS and preventing excessive activation of the NLRP3 inflammasome by IMQ. Thus, mtROS is a key driver of IMQ-induced NLRP3 activation.