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

Paula Saz-Leal, Carlos del Fresno, Paola Brandi, Sarai Martínez-Cano, Otto M. Dungan, John D. Chisholm, William G. Kerr, David Sancho

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1118-1126
Number of pages9
JournalCell Reports
Volume25
Issue number5
DOIs
StatePublished - Oct 30 2018

Keywords

  • SHIP-1
  • glycolytic metabolism
  • innate immune memory
  • myeloid
  • trained immunity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Saz-Leal, P., del Fresno, C., Brandi, P., Martínez-Cano, S., Dungan, O. M., Chisholm, J. D., Kerr, W. G., & Sancho, D. (2018). Targeting SHIP-1 in Myeloid Cells Enhances Trained Immunity and Boosts Response to Infection. Cell Reports, 25(5), 1118-1126. https://doi.org/10.1016/j.celrep.2018.09.092