p16(INK4a) Plays Critical Role in Exacerbating Inflammaging in High Fat Diet Induced Skin.
p16(INK4a) Plays Critical Role in Exacerbating Inflammaging in High Fat Diet Induced Skin.
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p16INK4a 在加剧高脂肪饮食引起的皮肤炎症中发挥关键作用
DOI：
10.1155/2022/3415528
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发表时间：
2022
影响因子：
--
通讯作者：
Lin, JinDe
中科院分区：
文献类型：
--
作者：
Liang, Yan;Gu, Tianya;Peng, Su;Lin, Yi;Liu, JiaBao;Wang, Xiaoyan;Huang, Xin;Zhang, Xiaodong;Zhu, Jun;Zhao, Lin;Fan, Changyan;Wang, Guangyan;Gu, Xin;Lin, JinDe
长期高脂肪饮食（HFD）促进皮肤衰老的发病机制，但详细的机制尚不清楚，特别是炎症，最近出现了衰老和年龄相关疾病与炎症相关的途径。p16INK4a（以下简称p16）抑制细胞周期，p16缺失显著抑制炎症。我们观察到hfd诱导p16在皮肤中过表达。因此，我们研究了p16是否会加剧hfd诱导的皮肤炎症，以及p16缺失是否对这一过程具有保护作用。8周龄双敲除（KO） ApoE−/−p16−/−小鼠和ApoE−/−窝仔饲喂HFD 12周，分析其皮肤表型。我们使用组织病理学、rna测序（RNA-seq）、生物信息学分析和分子技术测量皮肤纤维化、衰老相关分泌表型（SASP）水平和整合素-炎性体途径激活。我们发现HFD通过激活NLRP3炎症小体通路，增加炎症浸润，并通过平衡促凋亡和抗凋亡分子的表达促进细胞凋亡，从而促进皮肤炎症。与ApoE−/−表型相比，p16敲除通过改善炎症浸润和促炎因子(白细胞介素-1β （IL-1β)、白细胞介素-6 （IL-6）和肿瘤坏死因子-α (TNF-α)）的表达来抑制皮肤纤维化，并减轻ApoE−/−小鼠模型中HFD诱导的皮肤炎症进展。RNA-seq显示p16 KO小鼠抑制整合素炎性体和NF-κB促炎途径的激活。p16缺失或p16阳性细胞清除可能是预防长期hfd诱导的皮肤老化的新策略。
Long term high fat diets (HFD) promote skin aging pathogenesis, but detailed mechanisms remain unclear especially for inflammaging, which has recently emerged as a pathway correlating aging and age-related disease with inflammation. p16INK4a (hereafter termed p16) inhibits the cell cycle, with p16 deletion significantly inhibiting inflammaging. We observed that HFD-induced p16 overexpression in the skin. Therefore, we investigated if p16 exacerbated inflammaging in HFD-induced skin and also if p16 deletion exerted protective effects against this process. Eight-week-old double knockout (KO) ApoE−/−p16−/− mice and ApoE−/− littermates were fed HFD for 12 weeks and their skin phenotypes were analyzed. We measured skin fibrosis, senescence-associated secretory phenotype (SASP) levels, and integrin-inflammasome pathway activation using histopathological, RNA-sequencing (RNA-seq), bioinformatics analysis, and molecular techniques. We found that HFD contributed to inflammaging in the skin by activating the NLRP3 inflammasome pathway, increasing inflammatory infiltration, and promoting apoptosis by balancing expression between proapoptotic and antiapoptotic molecules. p16 knockout, when compared with the ApoE−/− phenotype, inhibited skin fibrosis by ameliorating inflammatory infiltration and proinflammatory factor expression (Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)), and also alleviated inflammaging skin progress induced by HFD in the ApoE−/− mouse model. RNA-seq showed that p16 KO mice inhibited both integrin-inflammasome and NF-κB proinflammatory pathway activation. p16 deletion or p16 positive cell clearance could be a novel strategy preventing long term HFD-induced skin aging.
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DOI：
10.18632/aging.202640
发表时间：
2021-02-06
期刊：
Aging
影响因子：
--
作者：
Buj R;Leon KE;Anguelov MA;Aird KM
通讯作者：
Aird KM
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
3.7
作者：
Kim KA;Gu W;Lee IA;Joh EH;Kim DH
通讯作者：
Kim DH
影响因子：
8
作者：
Crescenzi, E.;Pacifico, F.;Leonardi, A.
通讯作者：
Leonardi, A.
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.