Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence

Sapey, Elizabeth; Greenwood, Hannah; Walton, Georgia M; Mann, Elizabeth H.; Love, Alexander; Aaronson, Natasha; Insall, Robert H.; Stockley, Robert A.; Lord, Janet M.

doi:10.1182/blood-2013-08-519520

Cited by 270 publications

(267 citation statements)

References 55 publications

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“…Migration was assessed using an Insall chamber (Weber Scientific International Ltd., Teddington, UK) as described previously (3).…”

Section: Neutrophil Migrationmentioning

confidence: 99%

“…Neutrophils are key effector cells during bacterial infections, with evidence of suboptimal immune responses in the elderly contributing to poor outcomes (2). Age is associated with reduced neutrophil migratory accuracy (3), phagocytosis (4), and neutrophil extracellular trap release by dying cells ("NETosis") (5) in vitro, although degranulation appears increased (3). Poor migratory accuracy, reduced bactericidal function, and enhanced degranulation may delay pathogen clearance and increase bystander tissue damage through excess protease activity.…”

mentioning

confidence: 99%

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Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin

Sapey

Patel

Greenwood

et al. 2017

Am J Respir Crit Care Med

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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).

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“…Migration was assessed using an Insall chamber (Weber Scientific International Ltd., Teddington, UK) as described previously (3).…”

Section: Neutrophil Migrationmentioning

confidence: 99%

mentioning

confidence: 99%

Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin

Sapey

Patel

Greenwood

et al. 2017

Am J Respir Crit Care Med

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“…1). This value ranges from 21 to +1, whereby +1 indicates perfect migration along the gradient (54,55). This index exhibits two disadvantages.…”

Section: Statistical Analysis Of Haptotactic Behaviormentioning

confidence: 99%

“…By additional multiplication of one minus the absolute value of SMI, information about migration in x direction is included in the CPI. The angle between the FMI and the directness could be replaced by the angle u used in the literature if the direction of the gradient is exactly known (54,55). In the case of chemokinesis, only random movements are observed and the angle may adopt any value, whereas the FMI will exhibit a low value and the CPI will be low as well.…”

Section: Statistical Analysis Of Haptotactic Behaviormentioning

confidence: 99%

A Haptotaxis Assay for Leukocytes Based on Surface-Bound Chemokine Gradients

Rink

Helmer

et al. 2015

The Journal of Immunology

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The migration of leukocytes in response to chemokine gradients is an important process in the homeostasis of the human immune system and inflammation. In vivo the migration takes place on the surface of the endothelium to which the chemokine gradient is immobilized via interaction with glycosaminoglycans. To study leukocyte migration in response to surface-bound chemokines, we generated chemokine gradients by a simple stamping method: agarose stamps were soaked with chemokine solution to form continuous chemokine gradients by diffusion. These gradients could be easily transferred to a petri dish surface by stamping. We show that neutrophil granulocytes recognize these gradients and migrate toward increasing chemokine concentrations dependent on the slope of the gradient. Single-cell responses were recorded, and statistical analyses of cell behavior and migration were performed. For analysis of chemotaxis/haptotaxis, we propose a chemotactic precision index that is broadly applicable, valid, and allows for a straightforward and rapid quantification of the precision by which cells follow the direction of a given gradient. The presented technique is very simple, cost-efficient, and can be broadly applied for generating defined and reproducible immobilized gradients of almost any protein on surfaces, and it is a valuable tool to study haptotaxis.

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“…5 In addition to T-cell subset modification, functional properties of T cells are also reported, such as alteration in the TCR/CD3 and CD28 signaling pathways. [6][7][8][9] The CD4+ Treg cells involved in immune tolerance with immunosuppressive properties are, by contrast, increased, and a disruption in the balance between the T-cell subpopulations is deleterious in terms of cancer prevention, progression and elimination.…”

Section: The Role Of Immune Senescence In the Development Of Cancermentioning

confidence: 99%

Aging and malignant hemopathies

et al. 2015

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Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence

Abstract: 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.

Cited by 270 publications

References 55 publications

Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin

Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin

A Haptotaxis Assay for Leukocytes Based on Surface-Bound Chemokine Gradients

Aging and malignant hemopathies

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