Targeting SHIP-1 in Myeloid Cells Enhances Trained Immunity and Boosts Response to Infection

TLDR

β‑Glucan‑induced trained immunity in myeloid cells confers long‑term protection against secondary infections, yet effective strategies to enhance this response remain undefined. Deletion or pharmacological inhibition of SHIP‑1 in myeloid cells amplifies β‑glucan‑trained macrophage cytokine production, Akt/mTOR signaling, glycolytic metabolism, and epigenetic modifications, resulting in heightened cytokine responses and superior protection against Candida albicans in mice and human cells, thereby establishing SHIP‑1 as a viable target to boost trained immunity.

Abstract

β-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 β-glucan-trained macrophages from mice with a myeloid-specific deletion of the phosphatase SHIP-1 (LysMΔSHIP-1) showed enhanced proinflammatory cytokine production in response to lipopolysaccharide. Following β-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 LysMΔSHIP-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.