Journal Article

Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis

Monaco, Maria Chiara, Power, Christopher, Branton, William G., McKenzie, Brienne A., Saito, Leina B., Major, Eugene O., Boghozian, Roobina, Lu, Jian-Qiang, Mamik, Manmeet K.

2018

Overview

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS of unknown cause that remains incurable. Inflammasome-associated caspases mediate the maturation and release of the proinflammatory cytokines IL-1β and IL-18 and activate the pore-forming protein gasdermin D (GSDMD). Inflammatory programmed cell death, pyroptosis, was recently shown to be mediated by GSDMD. Here, we report molecular evidence for GSDMD-mediated inflammasome activation and pyroptosis in both myeloid cells (macrophages/microglia) and, unexpectedly, in myelin-forming oligodendrocytes (ODCs) in the CNS of patients with MS and in the MS animal model, experimental autoimmune encephalomyelitis (EAE). We observed inflammasome activation and pyroptosis in human microglia and ODCs in vitro after exposure to inflammatory stimuli and demonstrate caspase-1 inhibition by the small-molecule inhibitor VX-765 in both cell types. GSDMD inhibition by siRNA transduction suppressed pyroptosis in human microglia. VX-765 treatment of EAE animals reduced the expression of inflammasome- and pyroptosis-associated proteins in the CNS, prevented axonal injury, and improved neurobehavioral performance. Thus, GSDMD-mediated pyroptosis in select glia cells is a previously unrecognized mechanism of inflammatory demyelination and represents a unique therapeutic opportunity for mitigating the disease process in MS and other CNS inflammatory diseases.

• Publisher: National Academy of Sciences
• Subject: Animal models / Apoptosis / Autoimmune diseases / Biological Sciences / Caspase / Caspase 1 - metabolism / Caspase Inhibitors - pharmacology / Caspase-1 / Cell activation / Cell death / Cells, Cultured / Central nervous system / Cytokines / Demyelination / Dipeptides - pharmacology / Experimental allergic encephalomyelitis / Experiments / Forming / Humans / Inflammasomes / Inflammatory diseases / Injury prevention / Interleukin 18 / Macrophages / Microglia / Models, Biological / Multiple sclerosis / Multiple Sclerosis - enzymology / Multiple Sclerosis - pathology / Myelin / Myeloid cells / Nervous system / Neuronal-glial interactions / Neuroscience / Oligodendrocytes / Oligodendroglia - enzymology / Oligodendroglia - pathology / para-Aminobenzoates - pharmacology / PNAS Plus / Pore formation / Proteins / Pyroptosis / Pyroptosis - drug effects / siRNA