Abstract
Neutrophil extracellular traps (NETs) are a recently discovered addition to the defensive armamentarium of neutrophils, assisting in the immune response against rapidly dividing bacteria. Although older adults are more susceptible to such infections, no study has examined whether aging in humans influences NET formation. We report that TNF-α-primed neutrophils generate significantly more NETs than unprimed neutrophils and that lipopolysaccharide (LPS)- and interleukin-8 (IL-8)-induced NET formation exhibits a significant age-related decline. NET formation requires generation of reactive oxygen species (ROS), and this was also reduced in neutrophils from older donors identifying a mechanism for reduced NET formation. Expression of IL-8 receptors (CXCR1 and CXCR2) and the LPS receptor TLR4 was similar on neutrophils from young and old subjects, and neutrophils challenged with phorbol-12-myristate-13-acetate (PMA) showed no age-associated differences in ROS or NET production. Taken together, these data suggest a defect in proximal signalling underlies the age-related decline in NET and ROS generation. TNF-α priming involves signalling through p38 MAP kinase, but activation kinetics were comparable in neutrophils from young and old donors. In a clinical setting, we assessed the capacity of neutrophils from young and older patients with chronic periodontitis to generate NETs in response to PMA and hypochlorous acid (HOCL). Neutrophil extracellular trap generation to HOCL, but not PMA, was lower in older periodontitis patients but not in comparison with age-matched controls. Impaired NET formation is thus a novel defect of innate immunity in older adults but does not appear to contribute to the increased incidence of periodontitis in older adults.
Highlights
Comprised of a DNA backbone decorated with histones and such granule-derived peptides and enzymes as myeloperoxidase (MPO), Accepted for publication 22 March 2014 neutrophil elastase and lactoferrin (Brinkmann et al, 2004), neutrophil extracellular traps (NETs) are a novel feature of the defensive armamentarium of neutrophils
Three key molecular processes underlie the formation of NETs, namely reactive oxygen species (ROS) generation, autophagy and the hypercitrullination of histones H3 and H4, a process catalysed by the calcium-dependent nuclear enzyme peptidylarginine deiminase 4 (PAD4) (Remijsen et al, 2011)
In the majority of NET studies published to date, resting neutrophils have been used in NET generation assays
Summary
Comprised of a DNA backbone decorated with histones and such granule-derived peptides and enzymes as myeloperoxidase (MPO), Accepted for publication 22 March 2014 neutrophil elastase and lactoferrin (Brinkmann et al, 2004), neutrophil extracellular traps (NETs) are a novel feature of the defensive armamentarium of neutrophils. Despite the fact that the granule-derived proteins resident on NETs retain their activity when bound to DNA (Parker et al, 2012), NETs are themselves not directly microbicidal (Menegazzi et al, 2012; Parker et al, 2012) Instead, these structures are thought to confer protection by neutralizing the virulence factors of invading microbes (Brinkmann et al, 2004) and via their immunomodulatory effects, which include activating the human complement system (Oehmcke et al, 2009) and enhancing the activity of bystander T cells (Tillack et al, 2012). H2O2, does not appear to be the active oxygen species that triggers NET generation, with this function attributed instead to its downstream products hypochlorous acid (HOCL) and singlet oxygen (Nishinaka et al, 2011; Palmer et al, 2012)
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