Role of SHIP-1 phosphatase in trained immunity modulation

• Autores: Paula Saz Leal
• Directores de la Tesis: David Sancho Madrid (dir. tes.), Carlos del Fresno Sánchez (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2018
• Idioma: inglés
• Número de páginas: 146
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Química
    • Bioquímica
  • Ciencias médicas
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • 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