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Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence.
- Source :
-
Blood [Blood] 2014 Jan 09; Vol. 123 (2), pp. 239-48. Date of Electronic Publication: 2013 Nov 04. - Publication Year :
- 2014
-
Abstract
- Immunosenescence is the functional deterioration of the immune system during natural aging. Despite increased susceptibility to bacterial infections in older adults, age-associated changes to neutrophil responses are only partially understood, and neutrophil migration has not been characterized in detail. Here we describe reduced chemotaxis but preserved chemokinesis toward a range of inflammatory stimuli in migrating neutrophils isolated from healthy older subjects. Cross-sectional data indicate that migratory behavior changes in the sixth decade of life. Crucially, aberrant migration may increase "bystander" tissue damage and heighten inflammation as a result of excess proteinase release during inaccurate chemotaxis, as well as reducing pathogen clearance. We show evidence of increased neutrophil proteinase activity in older adults, namely, raised levels of neutrophil proteinase substrate-derived peptides and evidence of primary granule release, associated with increased systemic inflammation. Inaccurate migration was causally associated with increased constitutive phosphoinositide 3-kinase (PI3K) signaling; untreated neutrophils from old donors demonstrated significant PI3K activation compared with cells from young donors. PI3K-blocking strategies, specifically inhibition of PI3Kγ or PI3Kδ, restored neutrophil migratory accuracy, whereas SHIP1 inhibition worsened migratory flaws. Targeting PI3K signaling may therefore offer a new strategy in improving neutrophil functions during infections and reduce inappropriate inflammation in older patients.
- Subjects :
- Adult
Age Factors
Aged
Aged, 80 and over
Cell Degranulation drug effects
Cell Degranulation immunology
Chemotaxis, Leukocyte drug effects
Cross-Sectional Studies
Cytokines metabolism
Cytokines pharmacology
Enzyme Activation
Humans
Immune System Diseases drug therapy
Immune System Diseases immunology
Interleukin-8 metabolism
Interleukin-8 pharmacology
Leukocyte Disorders drug therapy
Leukocyte Disorders immunology
Middle Aged
Myeloblastin metabolism
Neutrophils drug effects
Phosphatidylinositol 3-Kinases metabolism
Receptors, Cytokine metabolism
Signal Transduction
Young Adult
Aging immunology
Chemotaxis, Leukocyte immunology
Neutrophils immunology
Neutrophils metabolism
Phosphoinositide-3 Kinase Inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 123
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 24191150
- Full Text :
- https://doi.org/10.1182/blood-2013-08-519520