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

Hanzhi Luo; Wei Chieh Mu; Rajendra Karki; Hou Hsien Chiang; Mary Mohrin; Jiyung J. Shin; Rika Ohkubo; Keisuke Ito; Thirumala Devi Kanneganti; Danica Chen

doi:10.1016/j.celrep.2018.12.101

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

Hanzhi Luo
, Wei Chieh Mu
, Rajendra Karki
, Hou Hsien Chiang
, Mary Mohrin
, Jiyung J. Shin
, Rika Ohkubo
, Keisuke Ito
, Thirumala Devi Kanneganti
, Danica Chen

Research output: Contribution to journal › Article › peer-review

131 Scopus citations

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.

Original language	English
Pages (from-to)	945-954.e4
Journal	Cell Reports
Volume	26
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2018.12.101
State	Published - Jan 22 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Funding

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.). 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.).

Funders	Funder number
Chau Hoi Shuen Foundation	AI124346, DK98263, DK115577, AI101935
Honjo International Scholarship Foundation
PackerWentz Endowment
National Science Foundation Arctic Social Science Program	T32 AG000266
National Institutes of Health (NIH)	AG063404, R01 DK101885, R01 DK117481
National Institute on Aging	T32AG000266
Leukemia and Lymphoma Society
US Department of Agriculture National Institute of Food and Agriculture, Agriculture and Food Research Initiative
Harvard Stem Cell Institute
Siebel Stem Cell Institute

Keywords

NLRP3
SIRT2
SIRT3
SIRT7
aging
clonal hematopoiesis
hematopoietic stem cell
inflammasome
mitochondrial UPR
oxidative stress

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2018.12.101

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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.",

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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",

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language = "English",

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AU - Chiang, Hou Hsien

AU - Mohrin, Mary

AU - Shin, Jiyung J.

AU - Ohkubo, Rika

AU - Ito, Keisuke

AU - Kanneganti, Thirumala Devi

AU - Chen, Danica

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N2 - 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.

AB - 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.

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KW - clonal hematopoiesis

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KW - inflammasome

KW - mitochondrial UPR

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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