Research Article: Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly

Date Published: February 28, 2012

Publisher: Blackwell Publishing Ltd

Author(s): Feng Qian, Xiaomei Wang, Lin Zhang, Shu Chen, Marta Piecychna, Heather Allore, Linda Bockenstedt, Stephen Malawista, Richard Bucala, Albert C Shaw, Erol Fikrig, Ruth R Montgomery.


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.

Partial Text

Aging is associated with a progressive decline in immune function (immunosenescence), resulting in an increased susceptibility to infection and decreased response to vaccines (Pawelec, 1999). The adaptive immune system is affected by aging, with a well-documented dysregulation in humoral as well as cell-mediated immune responses (McGlauchlen & Vogel, 2003; Linton & Dorshkind, 2004). Recent studies have begun to document the impact of aging on the innate immune system, but age-related deficits, especially in human subjects, remain incompletely defined (Rosenstiel et al., 2008; Shaw et al., 2010).

We quantified the age-related production by monocytes of the cytokines IL-8, TNF-α, and MIF following stimulation with a wide range of TLR ligands. While unstimulated levels of IL-8 and TNF-α were equivalent between age groups, macrophage migration inhibitory factor (MIF), a cytokine with protean influences on inflammation, had higher basal levels in monocytes from older donors. In addition, we observed a higher representation at baseline of the signaling mediator NF-κB (p65) translocated to the nucleus of monocytes from older donors. These results are consistent with the increased proinflammatory milieu associated with elevated levels of cytokines in older individuals, so called inflammaging, or chronic, low-grade inflammation which may contribute to age-associated frailty, morbidity, and mortality (Franceschi et al., 2007).