Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis

Christina D. Camell; Patrick Günther; Aileen Lee; Emily L. Goldberg; Olga Spadaro; Yun Hee Youm; Andrzej Bartke; Gene B. Hubbard; Yuji Ikeno; Nancy H. Ruddle; Joachim Schultze; Vishwa Deep Dixit

doi:10.1016/j.cmet.2019.10.006

Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis

Christina D. Camell, Patrick Günther, Aileen Lee, Emily L. Goldberg, Olga Spadaro, Yun Hee Youm, Andrzej Bartke, Gene B. Hubbard, Yuji Ikeno, Nancy H. Ruddle, Joachim Schultze, Vishwa Deep Dixit

Biology of Aging Medical Discovery Team

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

97 Scopus citations

Abstract

During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT.

Original language	English (US)
Pages (from-to)	1024-1039.e6
Journal	Cell Metabolism
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2019.10.006
State	Published - Dec 3 2019

Bibliographical note

Funding Information:
We thank Genentech Inc. for providing the Nlrp3 -deficient mice and the mouse specific CD20mAb. We also thank the Yale Center on Genomic Analysis (YCGA) for RNA-seq studies and the P. Cresswell laboratory for confocal microscopy support. J.L.S. was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) ( SFB704 and SFB645 ) and under Germany’s Excellence Strategy— EXC2151-390873048 . C.D.C. was supported by AFAR (American Federation of Aging Research Postdoctoral transition fellowship, USA) and NIA ( K99AG058800 ; USA). E.L.G. was supported by AFAR (postdoctoral fellowship; USA) and NIA ( K99AG058800 ; USA). The Dixit laboratory is supported in part by NIH grants P01AG051459 , AI105097 , AG051459 , AR070811 , the Glenn Foundation on Aging Research , and the Cure Alzheimer’s Fund (USA) . A.B. was supported by R01AG019899 (USA). A.B. thanks J.J. Kopchick for providing GHRKO breeders.

Funding Information:
We thank Genentech Inc. for providing the Nlrp3-deficient mice and the mouse specific CD20mAb. We also thank the Yale Center on Genomic Analysis (YCGA) for RNA-seq studies and the P. Cresswell laboratory for confocal microscopy support. J.L.S. was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) (SFB704 and SFB645) and under Germany's Excellence Strategy?EXC2151-390873048. C.D.C. was supported by AFAR (American Federation of Aging Research Postdoctoral transition fellowship, USA) and NIA (K99AG058800; USA). E.L.G. was supported by AFAR (postdoctoral fellowship; USA) and NIA (K99AG058800; USA). The Dixit laboratory is supported in part by NIH grants P01AG051459, AI105097, AG051459, AR070811, the Glenn Foundation on Aging Research, and the Cure Alzheimer's Fund (USA). A.B. was supported by R01AG019899 (USA). A.B. thanks J.J. Kopchick for providing GHRKO breeders. C.D.C. carried out most experiments. A.L. E.L.G. O.S. and Y.H. assisted with experiments. Y.I. and G.B.H. performed pathological analysis. A.B. generated the GHRKO mouse model. P.G. and J.S. performed the bioinformatics analysis and interpretation. N.H.R provided ProxTom and HEC6ST-GFP reporter mice and insight into lymphatic vessels and HEVs within FALCs. C.D.C. and V.D.D. conceived the project, analyzed the data, and wrote the manuscript with input from all co-authors. The authors declare no competing interests.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

B cell depletion
IL-1 signaling
Nlrp3 inflammasome
adipose tissue B cells
age-associated B cells
aging
fat-associated lymphoid cluster
growth hormone receptor
inflammaging
lipolysis

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@article{c60948573d2a41ab88b2a12aa21db3d4,

title = "Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis",

abstract = "During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT.",

keywords = "B cell depletion, IL-1 signaling, Nlrp3 inflammasome, adipose tissue B cells, age-associated B cells, aging, fat-associated lymphoid cluster, growth hormone receptor, inflammaging, lipolysis",

author = "Camell, {Christina D.} and Patrick G{\"u}nther and Aileen Lee and Goldberg, {Emily L.} and Olga Spadaro and Youm, {Yun Hee} and Andrzej Bartke and Hubbard, {Gene B.} and Yuji Ikeno and Ruddle, {Nancy H.} and Joachim Schultze and Dixit, {Vishwa Deep}",

note = "Funding Information: We thank Genentech Inc. for providing the Nlrp3 -deficient mice and the mouse specific CD20mAb. We also thank the Yale Center on Genomic Analysis (YCGA) for RNA-seq studies and the P. Cresswell laboratory for confocal microscopy support. J.L.S. was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) ( SFB704 and SFB645 ) and under Germany{\textquoteright}s Excellence Strategy— EXC2151-390873048 . C.D.C. was supported by AFAR (American Federation of Aging Research Postdoctoral transition fellowship, USA) and NIA ( K99AG058800 ; USA). E.L.G. was supported by AFAR (postdoctoral fellowship; USA) and NIA ( K99AG058800 ; USA). The Dixit laboratory is supported in part by NIH grants P01AG051459 , AI105097 , AG051459 , AR070811 , the Glenn Foundation on Aging Research , and the Cure Alzheimer{\textquoteright}s Fund (USA) . A.B. was supported by R01AG019899 (USA). A.B. thanks J.J. Kopchick for providing GHRKO breeders. Funding Information: We thank Genentech Inc. for providing the Nlrp3-deficient mice and the mouse specific CD20mAb. We also thank the Yale Center on Genomic Analysis (YCGA) for RNA-seq studies and the P. Cresswell laboratory for confocal microscopy support. J.L.S. was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) (SFB704 and SFB645) and under Germany's Excellence Strategy?EXC2151-390873048. C.D.C. was supported by AFAR (American Federation of Aging Research Postdoctoral transition fellowship, USA) and NIA (K99AG058800; USA). E.L.G. was supported by AFAR (postdoctoral fellowship; USA) and NIA (K99AG058800; USA). The Dixit laboratory is supported in part by NIH grants P01AG051459, AI105097, AG051459, AR070811, the Glenn Foundation on Aging Research, and the Cure Alzheimer's Fund (USA). A.B. was supported by R01AG019899 (USA). A.B. thanks J.J. Kopchick for providing GHRKO breeders. C.D.C. carried out most experiments. A.L. E.L.G. O.S. and Y.H. assisted with experiments. Y.I. and G.B.H. performed pathological analysis. A.B. generated the GHRKO mouse model. P.G. and J.S. performed the bioinformatics analysis and interpretation. N.H.R provided ProxTom and HEC6ST-GFP reporter mice and insight into lymphatic vessels and HEVs within FALCs. C.D.C. and V.D.D. conceived the project, analyzed the data, and wrote the manuscript with input from all co-authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

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doi = "10.1016/j.cmet.2019.10.006",

language = "English (US)",

volume = "30",

pages = "1024--1039.e6",

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T1 - Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis

AU - Camell, Christina D.

AU - Günther, Patrick

AU - Lee, Aileen

AU - Goldberg, Emily L.

AU - Spadaro, Olga

AU - Youm, Yun Hee

AU - Bartke, Andrzej

AU - Hubbard, Gene B.

AU - Ikeno, Yuji

AU - Ruddle, Nancy H.

AU - Schultze, Joachim

AU - Dixit, Vishwa Deep

N1 - Funding Information: We thank Genentech Inc. for providing the Nlrp3 -deficient mice and the mouse specific CD20mAb. We also thank the Yale Center on Genomic Analysis (YCGA) for RNA-seq studies and the P. Cresswell laboratory for confocal microscopy support. J.L.S. was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) ( SFB704 and SFB645 ) and under Germany’s Excellence Strategy— EXC2151-390873048 . C.D.C. was supported by AFAR (American Federation of Aging Research Postdoctoral transition fellowship, USA) and NIA ( K99AG058800 ; USA). E.L.G. was supported by AFAR (postdoctoral fellowship; USA) and NIA ( K99AG058800 ; USA). The Dixit laboratory is supported in part by NIH grants P01AG051459 , AI105097 , AG051459 , AR070811 , the Glenn Foundation on Aging Research , and the Cure Alzheimer’s Fund (USA) . A.B. was supported by R01AG019899 (USA). A.B. thanks J.J. Kopchick for providing GHRKO breeders. Funding Information: We thank Genentech Inc. for providing the Nlrp3-deficient mice and the mouse specific CD20mAb. We also thank the Yale Center on Genomic Analysis (YCGA) for RNA-seq studies and the P. Cresswell laboratory for confocal microscopy support. J.L.S. was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) (SFB704 and SFB645) and under Germany's Excellence Strategy?EXC2151-390873048. C.D.C. was supported by AFAR (American Federation of Aging Research Postdoctoral transition fellowship, USA) and NIA (K99AG058800; USA). E.L.G. was supported by AFAR (postdoctoral fellowship; USA) and NIA (K99AG058800; USA). The Dixit laboratory is supported in part by NIH grants P01AG051459, AI105097, AG051459, AR070811, the Glenn Foundation on Aging Research, and the Cure Alzheimer's Fund (USA). A.B. was supported by R01AG019899 (USA). A.B. thanks J.J. Kopchick for providing GHRKO breeders. C.D.C. carried out most experiments. A.L. E.L.G. O.S. and Y.H. assisted with experiments. Y.I. and G.B.H. performed pathological analysis. A.B. generated the GHRKO mouse model. P.G. and J.S. performed the bioinformatics analysis and interpretation. N.H.R provided ProxTom and HEC6ST-GFP reporter mice and insight into lymphatic vessels and HEVs within FALCs. C.D.C. and V.D.D. conceived the project, analyzed the data, and wrote the manuscript with input from all co-authors. The authors declare no competing interests. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/12/3

Y1 - 2019/12/3

N2 - During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT.

AB - During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT.

KW - B cell depletion

KW - IL-1 signaling

KW - Nlrp3 inflammasome

KW - adipose tissue B cells

KW - age-associated B cells

KW - aging

KW - fat-associated lymphoid cluster

KW - growth hormone receptor

KW - inflammaging

KW - lipolysis

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DO - 10.1016/j.cmet.2019.10.006

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VL - 30

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ER -

Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis

Abstract

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Keywords

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