Mitochondrial Stress-Initiated Aberrant Activation of the NLRP3 Inflammasome Regulates the Functional Deterioration of Hematopoietic Stem Cell Aging

Cell Rep. 2019 Jan 22;26(4):945-954.e4. doi: 10.1016/j.celrep.2018.12.101.


Aging-associated defects in hematopoietic stem cells (HSCs) can manifest in their progeny, leading to aberrant activation of the NLRP3 inflammasome in macrophages and affecting distant tissues and organismal health span. Whether the NLRP3 inflammasome is aberrantly activated in HSCs during physiological aging is unknown. We show here that SIRT2, a cytosolic NAD+-dependent deacetylase, is required for HSC maintenance and regenerative capacity at an old age by repressing the activation of the NLRP3 inflammasome in HSCs cell autonomously. With age, reduced SIRT2 expression and increased mitochondrial stress lead to aberrant activation of the NLRP3 inflammasome in HSCs. SIRT2 overexpression, NLRP3 inactivation, or caspase 1 inactivation improves the maintenance and regenerative capacity of aged HSCs. These results suggest that mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome is a reversible driver of the functional decline of HSC aging and highlight the importance of inflammatory signaling in regulating HSC aging.

Keywords: NLRP3; SIRT2; SIRT3; SIRT7; aging; clonal hematopoiesis; hematopoietic stem cell; inflammasome; mitochondrial UPR; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cellular Senescence / genetics
  • Cellular Senescence / immunology*
  • Hematopoietic Stem Cells / immunology*
  • Inflammasomes / immunology*
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • Sirtuin 2 / genetics
  • Sirtuin 2 / immunology
  • Stress, Physiological / genetics
  • Stress, Physiological / immunology*


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Sirt2 protein, mouse
  • Sirtuin 2