Defect in mevalonate pathway induces pyroptosis in Raw 264.7 murine monocytes |
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Authors: | Annalisa Marcuzzi Elisa Piscianz Martina Girardelli Sergio Crovella Alessandra Pontillo |
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Institution: | (1) Medical Genetic Service, Institute for Maternal and Child Health “Burlo Garofolo”, Via dell’Istria, 65/1, 34137 Trieste, Italy;(2) Department of Reproductive and Developmental Sciences and Public Health Care, University of Trieste, 34137 Trieste, Italy;(3) Department of Genetics, Federal University of Pernambuco, Av. Academico H Ramos, Cidade Universitaria, 50, 740-530 Recife, Brazil |
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Abstract: | The inhibition of mevalonate pathway by the aminobisphosphonate alendronate (ALD) has been previously associated with an augmented
lipopolysaccharide-induced interleukin-1beta (IL-1β) secretion in monocytes, as demonstrated in an auto-inflammatory disease
known as mevalonate kinase deficiency (MKD). In this study we investigated the effect of ALD + LPS on monocyte cell line (Raw
264.7) death. ALD strongly augmented LPS-induced programmed cell death (PCD) as well as IL-1β secretion in Raw murine monocytes,
whereas necrosis was rather unaffected. ALD + LPS induced caspase-3 activation. Inhibition of IL-1β stimulation partially
restored cell viability. These findings suggest that the inhibition of mevalonate pathway, together with a bacterial stimulus,
induce a PCD partly sustained by the caspase-3-related apoptosis and partly by caspase-1-associated pyroptosis. The involvement
of pyroptosis is a novel hit in our cell model and opens discussions about its role in inflammatory cells with chemical or
genetic inhibition of mevalonate pathway. |
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