title: Reduced levels of cytosolic DNA sensor AIM2 are associated with impaired cytokine responses in healthy elderly.
abstract: OBJECTIVE
  Human aging is associated with remodeling of the immune system. While most studies on immunosenescence have focused on adaptive immunity, the effects of aging on innate immunity are not well understood. Here, we investigated whether aging affects cytokine responses to a wide range of well-defined pattern recognition receptor (PRR) ligands, such as ligands for Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), retinoic-acid-inducible gene-I like receptors (RLRs) and the cytosolic DNA sensor absent in melanoma 2 (AIM2).
  
  
  METHODS
  Blood was collected from 16 young (20-39 years) and 18 elderly (60-84 years) healthy participants. Pro-inflammatory cytokine (TNF-α, IL-1β, IL-6, and IL-8) production in a whole blood assay (WBA) after stimulation with TLR ligands (Pam3csk4, poly(I:C), LPS, CpG), CLR ligand (β-glucan), NLR ligand (MDP), RLR ligands (5'ppp-dsDNA and poly(I:C)/lyovec) and the AIM2 ligand (poly(dA:dT) was assessed by ELISA. TLR2 and TLR4 expression by leukocytes and monocytes was determined by flow-cytometry. Expression of AIM2 by peripheral blood mononuclear cells (PBMC) was assessed by qRT-PCR and Western blot.
  
  
  RESULTS
  Cytokine responses to Pam3csk4, poly(I:C) and CpG, β-glucan, MDP, 5'ppp-dsDNA and poly(I:C)/lyovec were comparable between young and old participants. We observed a higher IL-8 response following stimulation of elderly blood samples with the TLR4 ligand LPS, which was associated with higher proportions of TLR4 expressing monocytes. Interestingly, stimulation of whole blood cells with the AIM2 ligand poly(dA:dT) resulted in significantly lower cytokine responses in old participants. Moreover, these lower cytokine responses were associated with lower AIM2 protein expression and activation in PBMC of old participants.
  
  
  CONCLUSIONS
  Our findings reveal an age-dependent reduction of AIM2 expression and activation which may explain reduced cytokine responses to the cytosolic DNA mimic poly(dA:dT) in healthy elderly individuals. Reduced AIM2-mediated sensing with age may contribute to increased vulnerability to bacterial or viral infections in the elderly.
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: q.wang01@umcg.nl.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: Johanna.westra@umcg.nl.
authors.forename: Johanna
authors.initials: J
authors.lastname: Westra
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: k.s.m.van.der.geest@umcg.nl.
authors.forename: Kornelis S M
authors.initials: KS
authors.lastname: van der Geest
authors.affiliation: Department of Critical Care, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands; Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: j.moser@umcg.nl.
authors.forename: Jill
authors.initials: J
authors.lastname: Moser
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: j.bijzet@umcg.nl.
authors.forename: Johan
authors.initials: J
authors.lastname: Bijzet
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: t.kuiper@umcg.nl.
authors.forename: Timara
authors.initials: T
authors.lastname: Kuiper
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: plorencetti@gmail.com.
authors.forename: Pedro G
authors.initials: PG
authors.lastname: Lorencetti
authors.affiliation: Dept. of Internal Medicine,Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. Electronic address: Leo.Joosten@radboudumc.nl.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Dept. of Internal Medicine,Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. Electronic address: Mihai.Netea@radboudumc.nl.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: p.heeringa@umcg.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: e.brouwer@umcg.nl.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brouwer
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: m.boots@umcg.nl.
authors.forename: Annemieke M H
authors.initials: AM
authors.lastname: Boots
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D016207:Cytokines / Q000097:blood*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: C410167:AIM2 protein, human; D016207:Cytokines; D004268:DNA-Binding Proteins; D051193:Toll-Like Receptors
keywords: Absent in melanoma 2; Aging; Human; Innate immunity; Pattern recognition receptors