Summary The innate immune system is composed of a network of cells including neutrophils, NK and NKT cells, monocytes/macrophages, and dendritic cells that mediate the earliest interactions with pathogens. Age-associated defects are observed in the activation of all of these cell types, linked to compromised signal transduction pathways including the Toll-like Receptors. However, aging is also characterized by a constitutive pro-inflammatory environment (Inflamm-aging) with persistent low-grade innate immune activation that may augment tissue damage caused by infections in elderly individuals. Thus, immunosenescence in the innate immune system appears to reflect dysregulation, rather than exclusively impaired function.

Key Points Constitutive PI3K activity is associated with less accurate neutrophil migration in healthy aged adults. This is associated with increased primary granule release and neutrophil elastase activity and may contribute to inflammation and infection.

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.

COPD neutrophils are intrinsically different than cells from other studied populations in their chemotactic behavior and migratory structure. Differences are not due to surface expression of chemoattractant receptors but instead appear to be due to differences in cell signaling.

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Rationale: Dysregulated neutrophil functions with age and sepsis are described. Statins are associated with improved infection survival in some observational studies, but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro.Objectives: To assess neutrophil migratory accuracy with age during respiratory infections and determine if and how a statin intervention could alter these blunted responses.Methods: The migratory accuracy of blood neutrophils from young (aged ,35 yr) and old (aged .60 yr) patients in health and during a lower respiratory tract infection, community-acquired pneumonia, and pneumonia associated with sepsis was assessed with and without simvastatin. In vitro results were confirmed in a double-blind randomized clinical trial in healthy elders. Cell adhesion markers were assessed. Measurements and Main Results:In vitro neutrophil migratory accuracy in the elderly deteriorated as the severity of the infectious pulmonary insult increased, without recovery at 6 weeks. Simvastatin rescued neutrophil migration with age and during mild to moderate infection, at high dose in older adults, but not during more severe sepsis. Confirming in vitro results, high-dose (80-mg) simvastatin improved neutrophil migratory accuracy without impeding other neutrophil functions in a double-blind randomized clinical trial in healthy elders. Simvastatin modified surface adhesion molecule expression and activity, facilitating accurate migration in the elderly.Conclusions: Infections in older adults are associated with prolonged, impaired neutrophil migration, potentially contributing to poor outcomes. Statins improve neutrophil migration in vivo in health and in vitro in milder infective events, but not in severe sepsis, supporting their potential utility as an early intervention during pulmonary infections.Clinical trial registered with www.clinicaltrialsregister.eu (2011-002082-38).

HighlightsPhysical activity associates with neutrophil migration in the elderly.Effects occur independently of inflammation or surface receptor expression.Adiponectin levels may positively influence neutrophil migration.

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