Necroptosis contributes to chronic inflammation and fibrosis in aging liver.
Necroptosis contributes to chronic inflammation and fibrosis in aging liver.
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DOI：
10.1111/acel.13512
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发表时间：
2021-12
期刊：
影响因子：
7.8
通讯作者：
Deepa SS
中科院分区：
文献类型：
--
作者：
Mohammed S;Thadathil N;Selvarani R;Nicklas EH;Wang D;Miller BF;Richardson A;Deepa SS
炎症的特征是随着年龄的增长，低度慢性炎症增加，是衰老的标志，与各种年龄相关疾病密切相关，包括慢性肝病（CLD）和肝细胞癌（HCC）。由于坏死性凋亡是一种通过释放DAMP诱导炎症的细胞死亡途径，因此我们测试了年龄相关的坏死性凋亡增加导致衰老肝脏慢性炎症的假设。MLKL和MLKL寡聚体的磷酸化、坏死性凋亡的标志物以及RIPK 3和RIPK 1的磷酸化在老年小鼠的肝脏中相对于年轻小鼠显著上调，并且这种增加发生在生命的后半期（即，18个月后）。M1巨噬细胞标志物、促炎细胞因子（TNFα、IL 6和IL 1 β）表达和纤维化标志物均随年龄增长在肝脏中显著上调，坏死性凋亡的变化与炎症和纤维化的变化一致。与年轻小鼠相比，从老年小鼠中分离的肝细胞和肝巨噬细胞显示出坏死性凋亡标志物水平升高以及促炎细胞因子表达增加。使用坏死性凋亡抑制剂necrostatin-1 s（Nec-1 s）进行短期治疗，减少老年小鼠肝脏中的坏死性凋亡、M1巨噬细胞标志物、纤维化和细胞衰老，并减少促炎细胞因子的表达。因此，我们的数据首次表明，肝脏衰老与坏死性凋亡增加有关，坏死性凋亡有助于肝脏中的慢性炎症，这反过来似乎有助于肝纤维化和可能的CLD。随着年龄的增长，肝脏坏死性凋亡增加，促炎细胞因子和纤维化标志物的表达增加。肝细胞和肝巨噬细胞是老年小鼠肝脏发生坏死性凋亡的主要细胞类型。用坏死性凋亡抑制剂necrostatin-1 s（Nec-1 s）短期治疗，减少老年小鼠肝脏中的坏死性凋亡、促炎细胞因子表达和纤维化。
Inflammaging, characterized by an increase in low‐grade chronic inflammation with age, is a hallmark of aging and is strongly associated with various age‐related diseases, including chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we tested the hypothesis that age‐associated increase in necroptosis contributes to chronic inflammation in aging liver. Phosphorylation of MLKL and MLKL oligomers, markers of necroptosis, as well as phosphorylation of RIPK3 and RIPK1 were significantly upregulated in the livers of old mice relative to young mice and this increase occurred in the later half of life (i.e., after 18 months of age). Markers of M1 macrophages, expression of pro‐inflammatory cytokines (TNFα, IL6 and IL1β), and markers of fibrosis were all significantly upregulated in the liver with age and the change in necroptosis paralleled the changes in inflammation and fibrosis. Hepatocytes and liver macrophages isolated from old mice showed elevated levels of necroptosis markers as well as increased expression of pro‐inflammatory cytokines relative to young mice. Short‐term treatment with the necroptosis inhibitor, necrostatin‐1s (Nec‐1s), reduced necroptosis, markers of M1 macrophages, fibrosis, and cell senescence as well as reducing the expression of pro‐inflammatory cytokines in the livers of old mice. Thus, our data show for the first time that liver aging is associated with increased necroptosis and necroptosis contributes to chronic inflammation in the liver, which in turn appears to contribute to liver fibrosis and possibly CLD. Necroptosis increases with age in the liver and paralleled an increase in the expression of proinflammatory cytokines and markers of fibrosis. Hepatocytes and liver macrophages are the major cell types that undergo necroptosis in the livers of old mice. Short term treatment with the necroptosis inhibitor, necrostatin‐1s (Nec‐1s), reduced necroptosis, expression of proinflammatory cytokines and fibrosis in the livers of old mice.
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影响因子：
4.7
作者：
Fabregat I;Caballero-Díaz D
通讯作者：
Caballero-Díaz D
影响因子：
5.3
作者：
Faure-Dupuy, Suzanne;Vegna, Serena;Lucifora, Julie
通讯作者：
Lucifora, Julie
影响因子：
3
作者：
Higgins SJ;Xing K;Kim H;Kain DC;Wang F;Dhabangi A;Musoke C;Cserti-Gazdewich CM;Tracey KJ;Kain KC;Liles WC
通讯作者：
Liles WC
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
DOI：
10.1007/978-1-4939-6700-1_21
发表时间：
2017-01-01
期刊：
HEPATITIS B VIRUS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Liu, Jia;Huang, Xuan;Lu, Mengji
通讯作者：
Lu, Mengji