ABSTRACT
Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.
Subject(s)
Cysteine/analogs & derivatives , Dimethyl Fumarate/pharmacology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Familial Mediterranean Fever/drug therapy , Intracellular Signaling Peptides and Proteins/metabolism , Multiple Sclerosis/drug therapy , Phosphate-Binding Proteins/metabolism , Pyroptosis/drug effects , Animals , Caspases/metabolism , Citric Acid Cycle/drug effects , Cysteine/metabolism , Dimethyl Fumarate/therapeutic use , Female , HEK293 Cells , Humans , Inflammasomes/drug effects , Inflammasomes/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Lipopolysaccharides/immunology , Macrophage Activation , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Phosphate-Binding Proteins/genetics , Protein Processing, Post-Translational , Pyroptosis/immunologyABSTRACT
The detection of pathogens through nucleic acid sensors is a defining principle of innate immunity. RNA-sensing and DNA-sensing receptors sample subcellular compartments for foreign nucleic acids and, upon recognition, trigger immune signalling pathways for host defence. Over the past decade, our understanding of how the recognition of nucleic acids is coupled to immune gene expression has advanced considerably, particularly for the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signalling effector stimulator of interferon genes (STING), as well as the molecular components and regulation of this pathway. Moreover, the ability of self-DNA to engage cGAS has emerged as an important mechanism fuelling the development of inflammation and implicating the cGAS-STING pathway in human inflammatory diseases and cancer. This detailed mechanistic and biological understanding is paving the way for the development and clinical application of pharmacological agonists and antagonists in the treatment of chronic inflammation and cancer.
