Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly.
Aging is accompanied by a progressive decline in immune function. Studies have shown age-related decreases in the expression and signaling efficiency of Toll-like receptors (TLRs) in monocytes and dendritic cells and dysregulation of macrophage TLR3. Using a multivariable mixed effect model, we report a highly significant increase in TLR5-induced production of IL-8 from monocytes of older individuals (P < 0.0001). Elevated IL-8 is accompanied by increased expression of TLR5, both protein and mRNA, and by increased levels of TLR5-mediated phosphorylation of MAPK p38 and ERK. We noted incomplete activation of NF-κB in response to TLR5 signaling in monocytes of elderly donors, as reflected by the absence of an associated increase in the production of TNF-α. Elevated TLR5 may provide a critical mechanism to enhance immune responsiveness in older individuals.
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8031, USA.
Feng
F
Qian
Xiaomei
X
Wang
Lin
L
Zhang
Shu
S
Chen
Marta
M
Piecychna
Heather
H
Allore
Linda
L
Bockenstedt
Stephen
S
Malawista
Richard
R
Bucala
Albert C
AC
Shaw
Erol
E
Fikrig
Ruth R
RR
Montgomery
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D015999:Multivariate Analysis; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D012333:RNA, Messenger / Q000096:biosynthesis*; D015398:Signal Transduction / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases