TMEM11-Dependent Cristae Architecture Restrains Imiquimod-Induced NLRP3 Inflammasome Activation via Mitochondrial ROS
- 1UCLA
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.
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BibTeX
@misc{srikanth2026tmem11dependent,
title = {{TMEM11-Dependent Cristae Architecture Restrains Imiquimod-Induced NLRP3 Inflammasome Activation via Mitochondrial ROS}},
author = {S. Srikanth and B. Wu and M. Do and C. Beninca and V. ARumugaswami and Y. Gwack},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.764965},
url = {https://www.biorxiv.org/content/10.64898/2026.11.06.764965v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - TMEM11-Dependent Cristae Architecture Restrains Imiquimod-Induced NLRP3 Inflammasome Activation via Mitochondrial ROS
AU - S. Srikanth
AU - B. Wu
AU - M. Do
AU - C. Beninca
AU - V. ARumugaswami
AU - Y. Gwack
PY - 2026
DA - 2026/11/06
PB - bioRxiv
DO - 10.64898/2026.11.06.764965
UR - https://www.biorxiv.org/content/10.64898/2026.11.06.764965v1
AB - 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.
ER -