Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence
Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence
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DOI：
10.1182/blood-2013-08-519520
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发表时间：
2014-01-09
期刊：
影响因子：
20.3
通讯作者：
Lord, Janet M.
中科院分区：
文献类型：
--
作者：
Sapey, Elizabeth;Greenwood, Hannah;Lord, Janet M.
免疫衰老是免疫系统在自然衰老过程中的功能退化。尽管老年人对细菌感染的易感性增加，但与年龄相关的中性粒细胞反应变化仅部分了解，中性粒细胞迁移尚未详细描述。在这里，我们描述了减少趋化性，但保留对一系列炎性刺激迁移中性粒细胞从健康老年人受试者。横截面数据表明，迁移行为的变化，在第六个十年的生活。至关重要的是，异常迁移可能会增加“旁观者”组织损伤，并由于在不准确的趋化过程中过量的蛋白酶释放而加剧炎症，以及减少病原体清除。我们发现老年人中性粒细胞蛋白酶活性增加的证据，即中性粒细胞蛋白酶底物衍生肽水平升高和原发性颗粒释放的证据，与全身炎症增加相关。不准确的迁移与增加的组成型磷酸肌醇3-激酶（PI 3 K）信号传导有因果关系;与年轻供体的细胞相比，来自老年供体的未处理中性粒细胞表现出显著的PI 3 K活化。PI 3 K阻断策略，特别是PI 3 K γ或PI 3 K δ的抑制，恢复了中性粒细胞迁移的准确性，而SHIP 1抑制恶化了迁移缺陷。因此，靶向PI 3 K信号传导可能提供一种新的策略，以改善感染期间的中性粒细胞功能，并减少老年患者的不适当炎症。
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 PI3K gamma or PI3K delta, 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.