Sirt6 regulates dendritic cell differentiation, maturation, and function

Denise Lasigliè, Silvia Boero, Inga Bauer, Sara Morando, Patrizia Damonte, Michele Cea, Fiammetta Monacelli, Patrizio Odetti, Alberto Ballestrero, Antonio Uccelli, Raul Mostoslavsky, Alessandro Poggi, Alessio Nencioni

Research output: Contribution to journalArticle

Abstract

Dendritic cells (DCs) are antigen-presenting cells that critically influence decisions about immune activation or tolerance. Impaired DC function is at the core of common chronic disorders and contributes to reduce immunocompetence during aging. Knowledge on the mechanisms regulating DC generation and function is necessary to understand the immune system and to prevent disease and immunosenescence. Here we show that the sirtuin Sirt6, which was previously linked to healthspan promotion, stimulates the development of myeloid, conventional DCs (cDCs). Sirt6-knockout (Sirt6KO) mice exhibit low frequencies of bone marrow cDC precursors and low yields of bone marrow-derived cDCs compared to wild-type (WT) animals. Sirt6KO cDCs express lower levels of class II MHC, of costimulatory molecules, and of the chemokine receptor CCR7, and are less immunostimulatory compared to WT cDCs. Similar effects in terms of differentiation and immunostimulatory capacity were observed in human monocyte-derived DCs in response to SIRT6 inhibition. Finally, while Sirt6KO cDCs show an overall reduction in their ability to produce IL-12, TNF-α and IL-6 secretion varies dependent on the stimulus, being reduced in response to CpG, but increased in response to other Toll-like receptor ligands. In conclusion, Sirt6 plays a crucial role in cDC differentiation and function and reduced Sirt6 activity may contribute to immunosenescence.

Original languageEnglish
Pages (from-to)34-49
Number of pages16
JournalAging
Volume8
Issue number1
Publication statusPublished - 2016

Keywords

  • Costimulatory molecules
  • Dendritic cells
  • Immunosenescence
  • Sirt6
  • TNF-α
  • Toll-like receptor ligands

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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  • Cite this

    Lasigliè, D., Boero, S., Bauer, I., Morando, S., Damonte, P., Cea, M., Monacelli, F., Odetti, P., Ballestrero, A., Uccelli, A., Mostoslavsky, R., Poggi, A., & Nencioni, A. (2016). Sirt6 regulates dendritic cell differentiation, maturation, and function. Aging, 8(1), 34-49.