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 |
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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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