@article{92af50624199437e936f5fe69b5008f3,
title = "Mitochondrial Stress-Initiated Aberrant Activation of the NLRP3 Inflammasome Regulates the Functional Deterioration of Hematopoietic Stem Cell Aging",
abstract = " 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",
author = "Hanzhi Luo and Mu, {Wei Chieh} and Rajendra Karki and Chiang, {Hou Hsien} and Mary Mohrin and Shin, {Jiyung J.} and Rika Ohkubo and Keisuke Ito and Kanneganti, {Thirumala Devi} and Danica Chen",
note = "Funding Information: We thank R. Vance for discussion and reagents and H. Nolla, A. Valeros, and K. Heydari for cell sorting. Supported by NIH Grants R01 DK101885 (D.C.), R01 DK117481 (D.C.), and AG063404 (D.C.); National Institute of Food and Agriculture (D.C.); PackerWentz Endowment (D.C.); Chau Hoi Shuen Foundation (D.C.); Grants AI124346 (T.-D.K.), AI101935 (T.-D.K.), DK98263 (K.I.), and DK115577 (K.I.); the Leukemia and Lymphoma Society (K.I.); Glenn/AFAR Scholarship (H.L.); Dr. and Mrs. James C.Y. Soong Fellowship (H.-H.C., W.-C.M.); Government Scholarship for Study Abroad (GSSA) from Taiwan (W.-C.M.); NSF Fellowship (J.J.S.); NIH Grant T32 AG000266 (M.M. and J.J.S.); Siebel Stem Cell Institute (D.C. and M.M.); the ITO Scholarship (R.O.); and the Honjo International Scholarship (R.O.). Funding Information: We thank R. Vance for discussion and reagents and H. Nolla, A. Valeros, and K. Heydari for cell sorting. Supported by NIH Grants R01 DK101885 (D.C.), R01 DK117481 (D.C.), and AG063404 (D.C.); National Institute of Food and Agriculture (D.C.); PackerWentz Endowment (D.C.); Chau Hoi Shuen Foundation (D.C.); Grants AI124346 (T.-D.K.), AI101935 (T.-D.K.), DK98263 (K.I.), and DK115577 (K.I.); the Leukemia and Lymphoma Society (K.I.); Glenn/AFAR Scholarship (H.L.); Dr. and Mrs. James C.Y. Soong Fellowship (H.-H.C., W.-C.M.); Government Scholarship for Study Abroad (GSSA) from Taiwan (W.-C.M.); NSF Fellowship (J.J.S.); NIH Grant T32 AG000266 (M.M. and J.J.S.); Siebel Stem Cell Institute (D.C. and M.M.); the ITO Scholarship (R.O.); and the Honjo International Scholarship (R.O.). Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jan,
day = "22",
doi = "10.1016/j.celrep.2018.12.101",
language = "English (US)",
volume = "26",
pages = "945--954.e4",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}