Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/6661
Targeting SHIP-1 in Myeloid Cells Enhances Trained Immunity and Boosts Response to Infection
Saz-Leal, Paula CNIC | del Fresno, Carlos CNIC | Brandi, Paola CNIC | Martinez-Cano, Sarai CNIC | Dungan, Otto M. | Chisholm, John D. | Kerr, William G. | Sancho, David CNIC
Cell Rep. 2018; 25(5):1118-1126
beta-Glucan-induced trained immunity in myeloid cells leads to long-term protection against secondary infections. Although previous studies have characterized this phenomenon, strategies to boost trained immunity remain undefined. We found that beta-glucan-trained macrophages from mice with a myeloid-specific deletion of the phosphatase SHIP-1 (LysM Delta SHIP-1) showed enhanced proinflammatory cytokine production in response to lipopolysaccharide. Following beta-glucan training, SHIP-1-deficient macrophages exhibited increased phosphorylation of Akt and mTOR targets, correlating with augmented glycolytic metabolism. Enhanced training in the absence of SHIP-1 relied on histone methylation and acetylation. Trained LysM Delta SHIP-1 mice produced increased amounts of proinflammatory cytokines upon rechallenge in vivo and were better protected against Candida albicans infection compared with control littermates. Pharmacological inhibition of SHIP-1 enhanced trained immunity against Candida infection in mouse macrophages and human peripheral blood mononuclear cells. Our data establish proof of concept for improvement of trained immunity and a strategy to achieve it by targeting SHIP-1.
CANDIDA-ALBICANS INFECTION | IN-VIVO | INNATE IMMUNITY | MONOCYTES | PROTECTION | INFLAMMATION | REINFECTION | INDUCTION | VITRO