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

摘要

class="head no_bottom_margin" id="sec1title">IntroductionInnate immune cells challenged with certain stimuli undergo long-lasting changes that result in improved response to a second challenge by the same or different microbial insult, a process referred to as trained immunity (). Stimuli driving trained immunity lead to a shift to aerobic glycolysis (), accompanied by sustained changes in the epigenome, mainly via histone methylation and acetylation (). Among trained immunity inducers, exposure to a low dose of Candida albicans or the fungal cell wall component β-glucan protects mice from secondary lethal systemic candidiasis () or heterologous Staphylococcus aureus septicemia (). This acquired resistance does not rely on T/B lymphocytes or natural killer (NK) cells but occurs in a myeloid-dependent manner (, ).The C-type lectin receptor Dectin-1 is critical for Candida albicans or β-glucan sensing, leading to immune training of monocytes (). These primed macrophages show heightened production of proinflammatory cytokines to a wide variety of insults (, ). Dectin-1-mediated training relies on activation of the PI3K (phosphoinositide 3-kinase)/mTOR (mammalian target of rapamycin) pathway (). PI3K-induced Akt signaling is tightly regulated by phosphoinositide phosphatases, which counterbalance PI3K activity (). Among those phosphatases, the hematopoietic-restricted SHIP-1 (SH2-containing inositol 5′-phosphatase 1) () is of particular interest, as we showed that it binds to the intracellular tail of Dectin-1 receptor in granulocyte-macrophage colony-stimulating factor (GM-CSF) bone marrow-derived cells ().Because Candida albicans-induced trained immunity relies on Dectin-1 and PI3K signaling, and SHIP-1 couples to Dectin-1 and counteracts PI3K function, we postulated that SHIP-1 targeting could modulate trained immunity triggered by Dectin-1. Our results indicate that SHIP-1 has a regulatory role in β-glucan-induced training, affecting all hallmarks involved in that process. Moreover, in vivo SHIP-1 deficiency in the myeloid compartment improves protection conferred by trained immunity. Notably, enhanced proinflammatory cytokine production and better protection was also achieved by pharmacological SHIP-1 inhibition in both mice and human peripheral blood mononuclear cells (PBMCs), providing a potential therapeutic approach to boost trained immunity.