Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation.
Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation.
复制标题
通过阻断p38促丝分裂原激活蛋白（MAP）激酶诱导的炎症，增强皮肤免疫力。
DOI：
10.1016/j.jaci.2017.10.032
复制
发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Akbar AN
中科院分区：
文献类型：
--
作者：
Vukmanovic-Stejic M;Chambers ES;Suárez-Fariñas M;Sandhu D;Fuentes-Duculan J;Patel N;Agius E;Lacy KE;Turner CT;Larbi A;Birault V;Noursadeghi M;Mabbott NA;Rustin MHA;Krueger JG;Akbar AN
随着年龄的增长，免疫力下降，导致水痘带状疱疹病毒(VZV)的重新激活。在人类受试者中，与年龄相关的免疫变化通常是在血白细胞中测量的；然而，这可能不能反映组织特异性免疫的变化。我们在皮肤中使用VZV抗原挑战系统来研究组织特异性机制的变化，这些机制与衰老过程中对这种病毒的反应降低有关。我们根据皮内注射VZV抗原后红斑和硬结的程度来评估皮肤免疫力。我们还对年轻受试者(40岁)和老年受试者(65岁)的皮肤活检标本进行了免疫组织学和转录分析。与年轻人相比，老年人皮肤VZV抗原攻击部位红斑和硬结减少，CD4+和CD8+T细胞浸润减少，整体基因激活减弱。这与与p38丝裂原活化蛋白激酶相关的促炎细胞因子的产生有关的同一受试者皮肤无菌炎症的增加有关(P<；2.0007)。我们通过口服小分子p38丝裂原活化蛋白激酶抑制剂(losmapimod；英国布伦特福德的葛兰素史克)预处理来抑制老年受试者的全身炎症，该抑制剂降低了血清C反应蛋白水平和外周血单核细胞分泌IL-6和肿瘤坏死因子-α。相比之下，同一受试者对VZV抗原攻击的皮肤反应显著增加(P<；2.0003)。抗原攻击后早期皮肤的过度炎症会抑制抗原特异性免疫。然而，这种情况可以通过抑制炎性细胞因子的产生来逆转，这些炎性细胞因子可以用来提高疫苗的效力，并在衰老过程中治疗感染和恶性肿瘤。
Immunity decreases with age, which leads to reactivation of varicella zoster virus (VZV). In human subjects age-associated immune changes are usually measured in blood leukocytes; however, this might not reflect alterations in tissue-specific immunity. We used a VZV antigen challenge system in the skin to investigate changes in tissue-specific mechanisms involved in the decreased response to this virus during aging. We assessed cutaneous immunity based on the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsy specimens taken from the challenge site in young (<40 years) and old (>65 years) subjects. Old human subjects exhibited decreased erythema and induration, CD4+ and CD8+ T-cell infiltration, and attenuated global gene activation at the site of cutaneous VZV antigen challenge compared with young subjects. This was associated with increased sterile inflammation in the skin in the same subjects related to p38 mitogen-activated protein kinase–related proinflammatory cytokine production (P < .0007). We inhibited systemic inflammation in old subjects by means of pretreatment with an oral small-molecule p38 mitogen-activated protein kinase inhibitor (Losmapimod; GlaxoSmithKline, Brentford, United Kingdom), which reduced both serum C-reactive protein levels and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge were increased significantly in the same subjects (P < .0003). Excessive inflammation in the skin early after antigen challenge retards antigen-specific immunity. However, this can be reversed by inhibition of inflammatory cytokine production that can be used to promote vaccine efficacy and the treatment of infections and malignancy during aging.
登录
查看更多内容
DOI：
10.1084/jem.20090896
发表时间：
2009-08-31
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Agius E;Lacy KE;Vukmanovic-Stejic M;Jagger AL;Papageorgiou AP;Hall S;Reed JR;Curnow SJ;Fuentes-Duculan J;Buckley CD;Salmon M;Taams LS;Krueger J;Greenwood J;Klein N;Rustin MH;Akbar AN
通讯作者：
Akbar AN
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.2
作者：
MARRIE, TJ;JOHNSON, S;DURANT, H
通讯作者：
DURANT, H
影响因子：
16.6
作者：
Fourati S;Cristescu R;Loboda A;Talla A;Filali A;Railkar R;Schaeffer AK;Favre D;Gagnon D;Peretz Y;Wang IM;Beals CR;Casimiro DR;Carayannopoulos LN;Sékaly RP
通讯作者：
Sékaly RP
影响因子：
12.4
作者：
MOESGAARD, F;NIELSEN, ML;MOSBECH, H
通讯作者：
MOSBECH, H