Exposure of mononuclear phagocytes to β-glucan, a naturally occurring polysaccharide, contributes to the induction of innate immune memory, which is associated with long-term epigenetic, metabolic, and functional reprogramming. Although previous studies have shown that innate immune memory induced by β-glucan confers protection against secondary infections, its impact on autoinflammatory diseases, associated with inflammasome activation and IL-1β secretion, remains poorly understood. In particular, whether β-glucan–induced long-term reprogramming affects inflammasome activation in human macrophages in the context of these diseases has not been explored. We found that NLRP3 inflammasome–mediated caspase-1 activation and subsequent IL-1β production were reduced in β-glucan–reprogrammed macrophages. β-Glucan acted upstream of the NLRP3 inflammasome by preventing potassium (K+) efflux, mitochondrial ROS (mtROS) generation, and, ultimately, apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation. Importantly, β-glucan–induced memory in macrophages resulted in a remarkable attenuation of IL-1β secretion and caspase-1 activation in patients with an NLRP3-associated autoinflammatory disease, cryopyrin-associated periodic syndromes (CAPS). Our findings demonstrate that β-glucan–induced innate immune memory represses IL-1β–mediated inflammation and support its potential clinical use in NLRP3-driven diseases.
Giorgio Camilli, Mathieu Bohm, Alícia Corbellini Piffer, Rachel Lavenir, David L. Williams, Benedicte Neven, Gilles Grateau, Sophie Georgin-Lavialle, Jessica Quintin
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