Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, KY, United States.
Department of Kinesiology and Health Promotion, College of Education, University of Kentucky, Lexington, KY, United States.
Front Immunol. 2018 Mar 6;9:440. doi: 10.3389/fimmu.2018.00440. eCollection 2018.
Natural killer (NK) lymphocyte-mediated cytotoxicity and cytokine secretion control infections and cancers, but these crucial activities decline with age. NK cell development, homeostasis, and function require IL-15 and its chaperone, IL-15 receptor alpha (IL-15Rα). Macrophages and dendritic cells (DC) are major sources of these proteins. We had previously postulated that additional IL-15 and IL-15Rα is made by skeletal muscle and adipose tissue. These sources may be important in aging, when IL-15-producing immune cells decline. NK cells circulate through adipose tissue, where they may be exposed to local IL-15. The objectives of this work were to determine (1) if human muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) are sources of IL-15 and IL-15 Rα, and (2) whether any of these tissues correlate with NK cell activity in elderly humans. We first investigated IL-15 and IL-15Rα RNA expression in paired muscle and SAT biopsies from healthy human subjects. Both tissues expressed these transcripts, but IL-15Rα RNA levels were higher in SAT than in skeletal muscle. We also investigated tissue obtained from surgeries and found that SAT and VAT expressed equivalent amounts of IL-15 and IL-15Rα RNA, respectively. Furthermore, stromal vascular fraction cells expressed more IL-15 RNA than did adipocytes. To test if these findings related to circulating IL-15 protein and NK cell function, we tested 50 healthy adults aged > 70 years old. Plasma IL-15 levels significantly correlated with abdominal VAT mass in the entire cohort and in non-obese subjects. However, plasma IL-15 levels did not correlate with skeletal muscle cross-sectional area and correlated inversely with muscle strength. Plasma IL-15 did correlate with NK cell cytotoxic granule exocytosis and with CCL4 (MIP-1β) production in response to NKp46-crosslinking. Additionally, NK cell responses to K562 leukemia cells correlated inversely with muscle strength. With aging, immune function declines while infections, cancers, and deaths increase. We propose that VAT-derived IL-15 and IL-15Rα is a compensatory NK cell support mechanism in elderly humans.
自然杀伤 (NK) 淋巴细胞介导的细胞毒性和细胞因子分泌可控制感染和癌症，但这些关键活性随年龄增长而下降。NK 细胞的发育、稳态和功能需要白细胞介素 15 (IL-15) 和其伴侣白细胞介素 15 受体 alpha (IL-15Rα)。巨噬细胞和树突状细胞 (DC) 是这些蛋白的主要来源。我们之前假设，骨骼肌和脂肪组织也会产生额外的白细胞介素 15 和白细胞介素 15 受体 alpha。在衰老时，产生白细胞介素 15 的免疫细胞减少，这些来源可能很重要。NK 细胞循环通过脂肪组织，在那里它们可能会接触到局部的白细胞介素 15。这项工作的目的是确定 (1) 人体肌肉、皮下脂肪组织 (SAT) 和内脏脂肪组织 (VAT) 是否为白细胞介素 15 和白细胞介素 15 受体 alpha 的来源，以及 (2) 这些组织中的任何一个是否与老年人的 NK 细胞活性相关。我们首先研究了来自健康人体的配对肌肉和 SAT 活检中白细胞介素 15 和白细胞介素 15 受体 alpha 的 RNA 表达。这两种组织都表达了这些转录物，但 SAT 中的白细胞介素 15 受体 alpha RNA 水平高于骨骼肌。我们还研究了手术获得的组织，发现 SAT 和 VAT 分别表达等量的白细胞介素 15 和白细胞介素 15 受体 alpha RNA。此外，基质血管部分细胞表达的白细胞介素 15 RNA 多于脂肪细胞。为了测试这些发现是否与循环白细胞介素 15 蛋白和 NK 细胞功能有关，我们测试了 50 名年龄在 70 岁以上的健康成年人。整个队列和非肥胖受试者的血浆白细胞介素 15 水平与腹部 VAT 质量呈显著正相关。然而，血浆白细胞介素 15 水平与骨骼肌横截面积无关，与肌肉力量呈负相关。血浆白细胞介素 15 与 NK 细胞细胞毒性颗粒胞吐作用以及对 NKp46 交联的 CCL4 (MIP-1β) 产生呈正相关。此外，NK 细胞对 K562 白血病细胞的反应与肌肉力量呈负相关。随着年龄的增长，免疫功能下降，而感染、癌症和死亡增加。我们提出，VAT 衍生的白细胞介素 15 和白细胞介素 15 受体 alpha 是老年人 NK 细胞支持的代偿机制。
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