Department of Nutrition, Texas A&M University, College Station, TX, United States.
School of Kinesiology, University of Michigan, Ann Arbor, MI, United States.
Front Immunol. 2024 Aug 16;15:1357444. doi: 10.3389/fimmu.2024.1357444. eCollection 2024.
Chronic low-grade inflammation is a hallmark of aging, aka "inflammaging", which is linked to a wide range of age-associated diseases. Immune dysfunction increases disease susceptibility, and increases morbidity and mortality of aging. Innate immune cells, including monocytes, macrophages and neutrophils, are the first responders of host defense and the key mediators of various metabolic and inflammatory insults. Currently, the understanding of innate immune programming in aging is largely fragmented. Here we investigated the phenotypic and functional properties of innate immune cells in various peripheral tissues of young and aged mice under normal and endotoxic conditions. Under the steady state, aged mice showed elevated pro-inflammatory monocytes/macrophages in peripheral blood, adipose tissue, liver, and colon. Under lipopolysaccharide (LPS)-induced inflammatory state, the innate immune cells of aged mice showed a different response to LPS stimulus than that of young mice. LPS-induced immune responses displayed differential profiles in different tissues and cell types. In the peripheral blood, when responding to LPS, the aged mice showed higher neutrophils, but lower pro-inflammatory monocytes than that in young mice. In the peritoneal fluid, while young mice exhibited significantly elevated pro-inflammatory neutrophils and macrophages in response to LPS, aged mice exhibited decreased pro-inflammatory neutrophils and variable cytokine responses in macrophages. In the adipose tissue, LPS induced less infiltrated neutrophils but more infiltrated macrophages in old mice than young mice. In the liver, aged mice showed a more robust increase of pro-inflammatory macrophages compared to that in young mice under LPS stimulation. In colon, macrophages showed relatively mild response to LPS in both young and old mice. We have further tested bone-marrow derived macrophages (BMDM) from young and aged mice, we found that BMDM from aged mice have impaired polarization, displaying higher expression of pro-inflammatory markers than those from young mice. These data collectively suggest that innate immunity in peripheral tissues is impaired in aging, and the dysregulation of immunity is tissue- and cell-dependent. Our findings in the rodent model underscore the complexity of aging immunity. Further investigation is needed to determine whether the immune profile observed in aged mice is applicable in age-associated diseases in humans.
慢性低度炎症是衰老的标志，也称为“炎症衰老”，与多种与年龄相关的疾病有关。免疫功能障碍增加了疾病易感性，并增加了衰老的发病率和死亡率。先天免疫细胞，包括单核细胞、巨噬细胞和中性粒细胞，是宿主防御的第一反应者，也是各种代谢和炎症损伤的关键介质。目前，对衰老过程中先天免疫编程的理解还很零散。在这里，我们研究了在正常和内毒素条件下，年轻和年老小鼠各种外周组织中先天免疫细胞的表型和功能特性。在稳定状态下，年老小鼠在外周血、脂肪组织、肝脏和结肠中表现出升高的促炎单核细胞/巨噬细胞。在脂多糖（LPS）诱导的炎症状态下，年老小鼠的先天免疫细胞对 LPS 刺激的反应与年轻小鼠不同。LPS 诱导的免疫反应在不同组织和细胞类型中表现出不同的特征。在外周血中，当对 LPS 作出反应时，年老小鼠显示出比年轻小鼠更高的中性粒细胞，但更低的促炎单核细胞。在腹腔液中，年轻小鼠对 LPS 表现出明显升高的促炎中性粒细胞和巨噬细胞，而年老小鼠则表现出促炎中性粒细胞减少和巨噬细胞中细胞因子反应的变化。在脂肪组织中，与年轻小鼠相比，LPS 在老年小鼠中诱导的浸润中性粒细胞减少，但浸润巨噬细胞增加。在肝脏中，与年轻小鼠相比，LPS 刺激下老年小鼠的促炎巨噬细胞增加更为明显。在结肠中，年轻和年老小鼠的巨噬细胞对 LPS 的反应相对较温和。我们进一步测试了来自年轻和年老小鼠的骨髓来源的巨噬细胞（BMDM），发现来自年老小鼠的 BMDM 极化受损，其促炎标志物的表达高于年轻小鼠。这些数据共同表明，外周组织中的先天免疫在衰老过程中受损，免疫失调与组织和细胞有关。我们在啮齿动物模型中的发现强调了衰老免疫的复杂性。需要进一步研究以确定在年老小鼠中观察到的免疫特征是否适用于人类与年龄相关的疾病。
