Research Paper Volume 9, Issue 8 pp 1867—1884

p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli

Brandon M. Hall 1, , Vitaly Balan 1, , Anatoli S. Gleiberman 1, , Evguenia Strom 1, , Peter Krasnov 1, , Lauren P. Virtuoso 1, , Elena Rydkina 1, , Slavoljub Vujcic 1, , Karina Balan 1, , Ilya I. Gitlin 2, , Katerina I. Leonova 2, , Camila R. Consiglio 3, , Sandra O. Gollnick 2, , Olga B. Chernova 1, , Andrei V. Gudkov 1, 2, ,

  • 1 Everon Biosciences, Inc., Buffalo, NY 14203, USA
  • 2 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
  • 3 Department of Tumor Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

received: June 8, 2017 ; accepted: July 22, 2017 ; published: August 2, 2017 ;

https://doi.org/10.18632/aging.101268
How to Cite

Copyright: Hall et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Constitutive p16Ink4a expression, along with senescence-associated β-galactosidase (SAβG), are commonly accepted biomarkers of senescent cells (SCs). Recent reports attributed improvement of the healthspan of aged mice following p16Ink4a-positive cell killing to the eradication of accumulated SCs. However, detection of p16Ink4a/SAβG-positive macrophages in the adipose tissue of old mice and in the peritoneal cavity of young animals following injection of alginate-encapsulated SCs has raised concerns about the exclusivity of these markers for SCs. Here we report that expression of p16Ink4a and SAβG in macrophages is acquired as part of a physiological response to immune stimuli rather than through senescence, consistent with reports that p16Ink4a plays a role in macrophage polarization and response. Unlike SCs, p16Ink4a/SAβG-positive macrophages can be induced in p53-null mice. Macrophages, but not mesenchymal SCs, lose both markers in response to M1- [LPS, IFN-α, Poly(I:C)] and increase their expression in response to M2-inducing stimuli (IL-4, IL-13). Moreover, interferon-inducing agent Poly(I:C) dramatically reduced p16Ink4a expression in vivo in our alginate bead model and in the adipose tissue of aged mice. These observations suggest that the antiaging effects following eradication of p16Ink4a-positive cells may not be solely attributed to SCs but also to non-senescent p16Ink4a/SAβG-positive macrophages.

Abbreviations

AdMSC: mouse adipose-derived mesenchymal stromal cells, BMDM: bone marrow-derived macrophages, IFN: interferon, LPS: lipopolysaccharide, Poly(I:C): polyinosinic:polycytidylic acid, qPCR: quantitative real-time polymerase chain reaction, SAβG: senescence-associated β-galactosidase, SASP: senescence-associated secretory phenotype, SCs:senescent cells.