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

Autor: Mary Mohrin, Rika Ohkubo, Wei Chieh Mu, Hanzhi Luo, Rajendra Karki, Jiyung J. Shin, Danica Chen, Keisuke Ito, Hou Hsien Chiang, Thirumala-Devi Kanneganti
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Inflammasomes
Medical Physiology
Mice
Sirtuin 2
0302 clinical medicine
oxidative stress
Cellular Senescence
Mice
Knockout
integumentary system
Hematopoietic stem cell
Inflammasome
hemic and immune systems
mitochondrial UPR
Mitochondria
Cell biology
Haematopoiesis
Physiological Aging
medicine.anatomical_structure
Stem cell
medicine.drug
SIRT3
Knockout
Physiological
Caspase 1
NLR Family
Biology
Stress
SIRT2
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
NLRP3
Stress
Physiological
SIRT7
inflammasome
NLR Family
Pyrin Domain-Containing 3 Protein
clonal hematopoiesis
medicine
Animals
aging
Hematopoietic Stem Cells
Pyrin Domain-Containing 3 Protein
030104 developmental biology
hematopoietic stem cell
Biochemistry and Cell Biology
030217 neurology & neurosurgery
Zdroj: Cell Reports, 26 (4)
Cell reports, vol 26, iss 4
Cell reports
ISSN: 2666-3864
2211-1247
Popis: 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.
Cell Reports, 26 (4)
ISSN:2666-3864
ISSN:2211-1247
Databáze: OpenAIRE
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