Role of SHIP-1 phosphatase in trained immunity modulation
Author
Saz Leal, PaulaEntity
UAM. Departamento de BioquímicaDate
2018-12-14Subjects
Fosfatasas - Tesis doctorales; Inmunidad celular - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 14-12-2018Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
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, SHIP-
1-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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