2026-04-29T01:00:11Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/71672024-09-27T09:20:57Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
advisor
Sancho, David
advisor
del Fresno, Carlos
author
Sanz-Leal, Paula
funder
Ministerio de Economía, Industria y Competitividad (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Unión Europea. Comisión Europea
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Fundación ProCNIC
2019-02-12T14:43:40Z
2019-02-12T14:43:40Z
2018-12-14
http://hdl.handle.net/20.500.12105/7167
10.4321/repisalud.7167
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.
eng
Trained immunity
SHIP-1
Myeloid cell
Role of SHIP-1 phosphatase in trained immunity modulation
doctoral thesis
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
URL
https://repisalud.isciii.es/bitstreams/be90d400-b906-47b5-b311-0e87ef8429cc/download
File
MD5
f5e76b86d28c0b0ab84f84fd10a9e0e5
8389565
application/pdf
RoleofSHIP-1Phosphatase_2018.pdf
URL
https://repisalud.isciii.es/bitstreams/7ab427d6-99ef-4651-89fd-d30e22dd3a94/download
File
MD5
61743fa23cf3d8c391ba5fd6ce126f3b
404862
text/plain
RoleofSHIP-1Phosphatase_2018.pdf.txt