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

ABSTRACT: Exposure of mononuclear phagocytes to ?-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 ?-glucan confers protection against secondary infections, its impact on autoinflammatory diseases, associated with inflammasome activation and IL-1? secretion, remains poorly understood. In particular, whether ?-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? production were reduced in ?-glucan-reprogrammed macrophages. ?-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, ?-glucan-induced memory in macrophages resulted in a remarkable attenuation of IL-1? secretion and caspase-1 activation in patients with an NLRP3-associated autoinflammatory disease, cryopyrin-associated periodic syndromes (CAPS). Our findings demonstrate that ?-glucan-induced innate immune memory represses IL-1?-mediated inflammation and support its potential clinical use in NLRP3-driven diseases.

SUBMITTER: Camilli G 

PROVIDER: S-EPMC7456248 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature