Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage.
Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage.
复制标题
DOI：
10.1016/j.immuni.2021.04.025
复制
发表时间：
2021-07-13
期刊：
影响因子：
32.4
通讯作者：
Nourshargh S
中科院分区：
文献类型：
--
作者：
Barkaway A;Rolas L;Joulia R;Bodkin J;Lenn T;Owen-Woods C;Reglero-Real N;Stein M;Vázquez-Martínez L;Girbl T;Poston RN;Golding M;Saleeb RS;Thiriot A;von Andrian UH;Duchene J;Voisin MB;Bishop CL;Voehringer D;Roers A;Rot A;Lämmermann T;Nourshargh S
衰老与免疫功能失调有关。在这里，我们研究了年龄对中性粒细胞淤积的影响。使用共聚焦活体显微镜，我们发现在老年小鼠中，中性粒细胞粘附在炎症组织的血管内皮上，但表现出高频率的反向跨内皮迁移（rTEM）。中性粒细胞逆行破坏内皮是由位于内皮细胞（EC）连接处的肥大细胞产生的趋化因子CXCL1的增强所控制的。非典型趋化因子受体1 （ACKR1）的EC表达增加支持了老年小静脉中这种促炎环境。CXCL1的积累导致趋化因子受体CXCR2对中性粒细胞的脱敏，以及EC连接内中性粒细胞定向运动的丧失。荧光跟踪显示，在老年小鼠中，经过rTEM的中性粒细胞重新进入循环并扩散到肺部，在那里它们引起血管渗漏。因此，来自局部炎症部位的中性粒细胞有助于远程器官损伤，这意味着与衰老相关的全身炎症失调。肥大细胞（MC）和MC衍生的CXCL1驱动炎症老化组织中的中性粒细胞rTEM内皮细胞ACKR1-CXCL1轴增强促进中性粒细胞CXCR2内化老化的肺程序rTEM中性粒细胞向激活和有害表型发展老化是炎症疾病的关键危险因素。Barkaway、Rolas等人的研究表明，发炎的衰老组织以肥大细胞依赖的方式呈现出中性粒细胞反向跨内皮迁移（rTEM）回循环的高频率。rTEM中性粒细胞保留在老年肺中，并被编程为激活表型，能够诱导组织损伤。
Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM). This retrograde breaching of the endothelium by neutrophils was governed by enhanced production of the chemokine CXCL1 from mast cells that localized at endothelial cell (EC) junctions. Increased EC expression of the atypical chemokine receptor 1 (ACKR1) supported this pro-inflammatory milieu in aged venules. Accumulation of CXCL1 caused desensitization of the chemokine receptor CXCR2 on neutrophils and loss of neutrophil directional motility within EC junctions. Fluorescent tracking revealed that in aged mice, neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they caused vascular leakage. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging. Aged mice show high levels of neutrophil reverse transendothelial migration (rTEM) Mast cells (MC) and MC-derived CXCL1 drive neutrophil rTEM in inflamed aged tissues Intensified endothelial ACKR1-CXCL1 axis promotes neutrophil CXCR2 internalization Aged lungs program rTEM neutrophils toward an activated and noxious phenotype Aging is a critical risk factor for inflammatory disorders. Barkaway, Rolas et al. show that inflamed aged tissues present a high frequency of neutrophil reverse transendothelial migration (rTEM) back into the circulation in a mast cell-dependent manner. rTEM neutrophils are retained in aged lungs and programmed toward an activated phenotype, capable of inducing tissue damage.
登录
查看更多内容
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
30.5
作者：
Duchene J;Novitzky-Basso I;Thiriot A;Casanova-Acebes M;Bianchini M;Etheridge SL;Hub E;Nitz K;Artinger K;Eller K;Caamaño J;Rülicke T;Moss P;Megens RTA;von Andrian UH;Hidalgo A;Weber C;Rot A
通讯作者：
Rot A
影响因子：
5.5
作者：
Buckley, Christopher D.;Ross, Ewan A.;Rainger, G. Ed
通讯作者：
Rainger, G. Ed
影响因子：
15.9
作者：
Brandt, EB;Strait, RT;Rothenberg, ME
通讯作者：
Rothenberg, ME
DOI：
10.1038/s41569-018-0064-2
发表时间：
2018-09
期刊：
Nature reviews. Cardiology
影响因子：
--
作者：
Ferrucci L;Fabbri E
通讯作者：
Fabbri E