Age‐associated elevation in TLR5 leads to increased inflammatory responses in the elderly

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

doi:10.1111/j.1474-9726.2011.00759.x

Abstract

SummaryAging 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.

Highlights

Aging is associated with a progressive decline in immune function, resulting in an increased susceptibility to infection and decreased response to vaccines (Pawelec, 1999)
To further investigate the effects of aging on Toll-like receptors (TLRs) function, we have assessed age-related effects on signaling efficiency of monocytes stimulated by TLR ligands
We focused on IL-8 and TNF-a production, cytokines classically associated with TLR engagement, and macrophage migration inhibitory factor, MIF, a cytokine that amplifies the pro-inflammatory milieu (Metz & Bucala, 1997)

Summary

Introduction

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). Toll-like receptors (TLRs) are key components of the innate immune system that detect pathogen components and trigger antimicrobial host defense responses (Kawai & Akira, 2007). Recognition via TLRs initiates signal transduction pathways that control innate immune responses and facilitate the development of antigen-specific adaptive immunity (Takeda & Akira, 2005). Studies have shown reduced surface expression of TLRs 1 and 4 in monocytes of elderly human donors that correlates with an ageassociated reduction in TLR1 ⁄ 2 function, and a reduction in costimulatory

Results

Discussion

Conclusion