title: Growth Hormone Receptor Deficiency Protects against Age-Related NLRP3 Inflammasome Activation and Immune Senescence.
abstract: The hallmarks of age-related immune senescence are chronic inflammation, aberrant expansion of effector memory, and loss of naive T lymphocytes due in part to systemic activation of innate immune sensor NLRP3 inflammasome in myeloid lineage cells. The endogenous mechanisms that regulate inflammasome activation during aging are unknown. Here, we present evidence that growth hormone receptor (GH-R)-dependent downregulation of NLRP3 inflammasome in macrophages is linked to pro-longevity effects that maintain immune system homeostasis in aging. Deletion of GH-R prevented the macrophage-driven age-related activation of inflammasome in response to NLRP3 ligands and also increased the preservation of naive T cells, even in advanced age and with higher IFNγ secretion from effector cells. The mechanism of inflammasome inhibition is linked to autocrine somatotropic axis as ablation of IGF1R in macrophages lowered the NLRP3 inflammasome activation. Together, our findings show that functional somatotropic axis in macrophages controls inflammation, thus linking NLRP3-mediated innate immune signaling to health span and longevity.
authors.affiliation: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Spadaro
authors.affiliation: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Goldberg
authors.affiliation: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Christina D
authors.initials: CD
authors.lastname: Camell
authors.affiliation: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Youm
authors.affiliation: Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
authors.affiliation: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Kim Y
authors.initials: KY
authors.lastname: Nguyen
authors.affiliation: Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62701, USA.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bartke
authors.affiliation: Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35203, USA.
authors.forename: Liou Y
authors.initials: LY
authors.lastname: Sun
authors.affiliation: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: vishwa.dixit@yale.edu.
authors.forename: Vishwa Deep
authors.initials: VD
authors.lastname: Dixit
mesh_terms: D000375:Aging / Q000235:genetics* / Q000276:immunology; D000818:Animals; D019898:Autocrine Communication; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000276:immunology; D007113:Immunity, Innate; D007156:Immunologic Memory; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008136:Longevity / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D011986:Receptors, Somatotropin / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011986:Receptors, Somatotropin; D007371:Interferon-gamma; D017526:Receptor, IGF Type 1