Presenter of 1 Presentation
NOX2-DERIVED ROS CONTROL THE INFLAMMATORY RESPONSE BY REGULATING GASDERMIN D CLEAVAGE
Abstract
Background and Aims
Chronic Granulomatous Disease is a mendelian disorder caused by loss-of-function mutations genes encoding subunits of the NADPH oxidase complex 2. Increasing reports have underlined the role of the NLRP3 inflammasome in the pathophysiology of inflammation in CGD. However, the precise mechanism provoking a disproportionate inflammatory response in CGD patients remains elusive. Interestingly, the NOX2-deficiency model – characterized by defective production of cytosolic Reactive Oxygen Species (ROS) is at odds with the classical concept that chronic inflammation is caused by prolonged and sustained ROS production. These opposite views suggest that efficient regulation of the inflammatory response requires a well-balanced ROS signaling.
The objective of our study is to refine the precise role of cytosolic ROS in regulating inflammation and discover alternative strategies for treating chronic inflammatory diseases.
Methods
We assessed the dynamics of the inflammatory response in NOX2-deficient patients’ primary monocytes and a CRISPR-engineered NOX2-deficient phagocytic THP-1 cell line.
Results
We show that the defective redox signaling in CGD phagocytes is responsible for post-translational priming of the pyroptosome as evidenced by an enhanced oligomerization of its principal component ASC. NOX2 deficiency also increases the phosphorylation of GasderminD (GSDMD) at Serine 252, an amino acid that seems critical for its pyroptotic activity. Interestingly, GSDMD cleavage further activates the NLRP3 inflammasome by facilitating the release of mitochondrial DNA in the cytosol and by lowering the intracellular K+ concentration through GSDMD membrane pores.
Conclusions
We unveil the pivotal role of GSDMD in the amplification of the inflammatory response in CGD, paving the way for targeted therapies.