-Glucan-induced reprogramming of human macrophages inhibits NLRP3 inflammasome activation in cryopyrinopathies

Exposure of mononuclear phagocytes to [beta]-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 [beta]-glucan confers protection against secondary infections, its impact on autoinflammatory diseases, associated with inflammasome activation and IL-1[beta] secretion, remains poorly understood. In particular, whether [beta]-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-1[beta] production were reduced in [beta]-glucan-reprogrammed macrophages. [beta]-glucan acted upstream of the NLRP3 inflammasome by preventing potassium (1C) efflux, mitochondrial ROS (mtROS) generation, and, ultimately, apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation. Importantly, [beta]-glucan-induced memory in macrophages resulted in a remarkable attenuation of IL-1[beta] secretion and caspase-1 activation in patients with an NLRP3-associated autoinflammatory disease, cryopyrin-associated periodic syndromes (CAPS). Our findings demonstrate that [beta]-glucan-induced innate immune memory represses IL-1[beta]-mediated inflammation and support its potential clinical use in NLRP3-driven diseases.
Introduction Over the past decades, multiple studies have described memory phenotypes in innate immune cells, e.g., mononuclear phagocytes. The concept of innate immune memory refers to a change in the [...]