@article{5627a1110cac42ff8e7d4416e870660a,
title = "Targeting SHIP-1 in Myeloid Cells Enhances Trained Immunity and Boosts Response to Infection",
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. Trained immunity leads to long-term protection, but strategies to boost it require further investigation. Saz-Leal et al. show that myeloid SHIP-1 deletion enhances trained immunity, improving the response to pathogen-specific or heterologous challenges. Pharmacological inhibition of SHIP-1 also potentiates this phenomenon, thereby revealing a potential tool to harness trained immunity.",
keywords = "SHIP-1, glycolytic metabolism, innate immune memory, myeloid, trained immunity",
author = "Paula Saz-Leal and {del Fresno}, Carlos and Paola Brandi and Sarai Mart{\'i}nez-Cano and Dungan, {Otto M.} and Chisholm, {John D.} and Kerr, {William G.} and David Sancho",
note = "Funding Information: We thank the members of the Immunobiology Lab for useful discussions. We thank the CNIC facilities and personnel, particularly Santiago Rodr{\'i}guez and Ruben Mota, for their support. P.S.-L. is funded by grant BES-2015-072699 (“Ayudas para Contratos Predoctorales para la Formaci{\'o}n de Doctores 2015”) from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO). C.d.F. is supported by the Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer (AECC) Foundation as a recipient of an “Ayuda Fundaci{\'o}n Cient{\'i}fica AECC a Personal Investigador en Cancer” grant. Work in the Sancho laboratory is funded by CNIC and grant SAF2016-79040-R from MINECO , Agencia Estatal de Investigaci{\'o}n , and FEDER ( European Fund for Regional Development ); grant B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid ; grant RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III , MINECO , and FEDER ; Foundation Acteria ; a Constantes y Vitales prize (Atresmedia); Foundation La Marat{\'o} de TV3 (grant 201723 ); the European Commission (grant 635122-PROCROP H2020 ); and the European Research Council (ERC-2016-Consolidator Grant 725091 ). CNIC is supported by MINECO and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence ( MINECO award SEV-2015-0505 ). W.G.K. is an Empire Scholar of the State of New York, the Murphy Family Professor of Children{\textquoteright}s Oncology Research, and is supported by funds from the Paige Arnold Butterfly Run . Funding Information: We thank the members of the Immunobiology Lab for useful discussions. We thank the CNIC facilities and personnel, particularly Santiago Rodr{\'i}guez and Ruben Mota, for their support. P.S.-L. is funded by grant BES-2015-072699 (“Ayudas para Contratos Predoctorales para la Formaci{\'o}n de Doctores 2015”) from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO). C.d.F. is supported by the Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer (AECC) Foundation as a recipient of an “Ayuda Fundaci{\'o}n Cient{\'i}fica AECC a Personal Investigador en Cancer” grant. Work in the Sancho laboratory is funded by CNIC and grant SAF2016-79040-R from MINECO, Agencia Estatal de Investigaci{\'o}n, and FEDER (European Fund for Regional Development); grant B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; grant RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MINECO, and FEDER; Foundation Acteria; a Constantes y Vitales prize (Atresmedia); Foundation La Marat{\'o} de TV3 (grant 201723); the European Commission (grant 635122-PROCROP H2020); and the European Research Council (ERC-2016-Consolidator Grant 725091). CNIC is supported by MINECO and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). W.G.K. is an Empire Scholar of the State of New York, the Murphy Family Professor of Children's Oncology Research, and is supported by funds from the Paige Arnold Butterfly Run. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = oct,
day = "30",
doi = "10.1016/j.celrep.2018.09.092",
language = "English (US)",
volume = "25",
pages = "1118--1126",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}