Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7167
Role of SHIP-1 phosphatase in trained immunity modulation
Sanz-Leal, Paula CNIC
Date of defense
β-glucan-induced trained immunity in monocytes confers long-term protection against secondary infections through activation of the dendritic cell-associated C-type lectin 1 (Dectin-1)/ Phosphoinositide 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway. While previous studies have addressed the characterization of this phenomenon, strategies to boost trained immunity deserve further investigation. Src homology 2 (SH2) domain-containing inositol 5'-phosphatase (SHIP)-1 is a hematopoietic-restricted phosphatase that limits PI3K activity and it is able to associate with Dectin-1 receptor. Therefore, we hypothesized that SHIP-1 targeting could modulate trained immunity mediated by Dectin-1 ligands.Herein, we found that β-glucan-trained macrophages from mice with a myeloidspecific SHIP-1 deletion (LysMΔSHIP-1) enhanced proinflammatory cytokine production in response to lipopolysaccharide (LPS). Following β-glucan training, SHIP1-deficient macrophages exhibited increased phosphorylation of protein kinase B (also known as Akt, a downstream target of PI3K), and mTOR targets. These overactivation of the signaling pathway correlated with augmented glycolytic metabolism. Furthermore, enhanced training in the absence of SHIP-1 relied on epigenetic reprogramming, including histone methylation and acetylation. Trained LysMΔSHIP-1 mice produced increased proinflammatory cytokines upon rechallenge in vivo and were better protected against systemic Candida albicans infection compared with control littermates. Pharmacological inhibition of SHIP-1 enhanced trained immunity in vitro in mouse macrophages and human peripheral blood mononuclear cells (hPBMCs), and also improved protection conferred by immune training with C. albicans. These data establish a proof of concept for improvement of trained immunity, and place SHIP-1 as a target to achieve it.
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