Mesencephalic astrocyte-derived neurotrophic factor reprograms macrophages to ameliorate acetaminophen-induced acute liver injury via p38 MAPK pathway.
Mesencephalic astrocyte-derived neurotrophic factor reprograms macrophages to ameliorate acetaminophen-induced acute liver injury via p38 MAPK pathway.
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中脑星形胶质细胞源性神经营养因子通过 p38 MAPK 通路重编程巨噬细胞以改善对乙酰氨基酚诱导的急性肝损伤
DOI：
10.1038/s41419-022-04555-9
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发表时间：
2022-02-02
影响因子：
9
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Hou X;Liu Q;Gao Y;Yong L;Xie H;Li W;Zhou Y;Liu J;Feng L;Xu L;Shen Y;Wang H
对乙酰氨基酚（APAP）诱导的肝损伤（AILI）是急性肝功能衰竭的最常见原因，但其潜在机制仍不清楚。巨噬细胞和内质网应激在AILI的发病机制中起重要作用。中脑星形胶质细胞源性神经营养因子（MANF）是一种新发现的可溶性蛋白质，其表达和分泌受内质网应激的刺激。为探讨骨髓细胞MANF在AILI发病机制中的作用，我们检测了AILI模型小鼠和药物性肝损伤（DILI）患者的血清和肝脏样品。我们证明了MANF的水平在DILI患者和AILI小鼠中升高。此外，产生并使用骨髓特异性MANF敲除小鼠。观察到与野生型小鼠相比，APAP过量后骨髓特异性MANF基因敲除小鼠的肝脏恢复延迟。骨髓细胞中的MANF缺乏导致浸润性单核细胞衍生的巨噬细胞（MoMFs）增加，但APAP治疗后恢复性Ly 6Clow巨噬细胞减少。补充MANF增加了恢复性Ly 6Clow巨噬细胞，随后减轻了肝损伤。MANF还可通过p38 MAPK途径增强巨噬细胞IL-10的表达和吞噬功能。总之，MANF似乎是通过减少和重编程MoMF促进肝脏修复的关键免疫调节剂。MANF可能通过p38 MAPK途径，特别是通过增强IL-10和吞噬作用，促进促炎MoMFs向促修复Ly 6Clow MoMFs的表型转化。
Acetaminophen (APAP)-induced liver injury (AILI) is the most frequent cause of acute liver failure; but the underlying mechanisms still remain obscure. Macrophages and endoplasmic reticulum (ER) stress play an important role in the pathogenesis of AILI. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified 18-kDa soluble protein, whose expression and secretion are stimulated by ER stress. To investigate the role of myeloid cell MANF in the pathogenesis of AILI, we assayed serum and liver samples from AILI model mice and patients with drug-induced liver injury (DILI). We demonstrated that the levels of MANF were elevated in patients with DILI and in mice with AILI. Moreover, myeloid-specific MANF knockout mice were generated and used. It was observed that a delayed liver recovery from myeloid-specific MANF gene knockout mice following APAP overdose compared to that from wild-type mice. MANF deficiency in myeloid cells resulted in increased infiltrating monocyte-derived macrophages (MoMFs) but reduced restorative Ly6Clow macrophages after APAP treatment. MANF supplementation increased restorative Ly6Clow macrophages and subsequently alleviated liver injury. Moreover, MANF could enhance IL-10 expression and phagocytosis in macrophages via p38 MAPK pathway. Altogether, MANF seems to be a critical immune modulator in promoting liver repair via reducing and reprogramming MoMFs. MANF perhaps promoted the phenotype conversion of pro-inflammatory MoMFs to pro-restorative Ly6Clow MoMFs via p38 MAPK pathway, particularly through enhancing IL-10 and phagocytosis.
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DOI：
10.1126/science.aaf3646
发表时间：
2016-07-01
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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2004-01-05
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Cheng G
DOI：
10.1084/jem.20141539
发表时间：
2015-04-06
期刊：
The Journal of experimental medicine
影响因子：
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Dal-Secco D;Wang J;Zeng Z;Kolaczkowska E;Wong CH;Petri B;Ransohoff RM;Charo IF;Jenne CN;Kubes P
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Kubes P
DOI：
10.1073/pnas.1207290109
发表时间：
2012-07-10
影响因子：
11.1
作者：
Risco, Ana;del Fresno, Carlos;Cuenda, Ana
通讯作者：
Cuenda, Ana
影响因子：
13.5
作者：
Gao, Rachel Y.;Wang, Meng;Ju, Cynthia
通讯作者：
Ju, Cynthia