Pharmacological Inhibition of CCR2/5 Signaling Prevents and Reverses Alcohol-Induced Liver Damage, Steatosis, and Inflammation in Mice.
Pharmacological Inhibition of CCR2/5 Signaling Prevents and Reverses Alcohol-Induced Liver Damage, Steatosis, and Inflammation in Mice.
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CCR2/5信号的药理抑制可防止和逆转小鼠酒精诱导的肝损伤，脂肪变性和炎症。
DOI：
10.1002/hep.30249
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Szabo G
中科院分区：
文献类型：
--
作者：
Ambade A;Lowe P;Kodys K;Catalano D;Gyongyosi B;Cho Y;Iracheta-Vellve A;Adejumo A;Saha B;Calenda C;Mehta J;Lefebvre E;Vig P;Szabo G
枯否细胞（KC）和巨噬细胞（MMPs）的活化有助于酒精性肝病（ALD）中的脂肪变性、炎症和纤维化。我们发现酒精性肝病患者肝脏中MCL 2、T细胞和Ccr 2、Ccr 5表达频率增加，酒精性肝炎患者循环趋化因子CCL 2、CCL 5增加。我们假设用双重CCR 2/5抑制剂赛尼克韦罗（CVC）抑制CCL 2信号传导将减弱ALD。在ALD的小鼠模型中，肝损伤（ALT）和脂肪变性通过CVC预防，无论是在整个酒精喂养期间作为“预防”施用还是在ALD发展后作为“治疗”开始施用。酒精诱导的早期肝纤维化标志物（红葡萄糖、羟脯氨酸和胶原蛋白-1）的增加通过两种CVC施用模式而正常化。我们发现，用CVC“预防”和“治疗”逆转了TNFα、IL-1β、IL-6和CCL 2的肝脏mRNA和蛋白质表达的酒精相关增加。CVC给药方案防止了酒精喂养的小鼠肝脏中浸润性MMPs（F4/80 lo CD 11bhi）的增加并减少了促炎性Ly 6CHi MMPs。CVC增加了肝脏T细胞数量并减弱了IL-2表达，而对CD 69+或CD 25 + T细胞表达没有影响。在体外，CVC抑制CCL 2诱导的肝细胞Fasn和Adrp的增加，同时增加Acox-1、Pgc 1 α和Ucp-2的表达，这表明了减弱肝细胞脂肪变性的机制。我们发现，CCL 2和CCL 5使肝细胞对LPS诱导的肝损伤（TNFα、ALT和LDH释放）敏感。酒精喂养诱导肝脏中的细胞凋亡（PARP和半胱天冬酶-3裂解）和焦亡（gasdermin D裂解），并且CVC防止这两种形式的细胞死亡。总之，我们的数据证明了CVC抑制CCR 2/CCR 5作为改善酒精诱导的脂肪性肝炎和肝损伤的有效干预的临床前证据。
Kupffer cell (KC) and macrophage (MØ) activation contribute to steatosis, inflammation and fibrosis in alcoholic liver disease (ALD). We found increased frequency of MØ, T cells and expression of Ccr2 and Ccr5 in the livers of patients with ALD and increased circulating chemokines, CCL2 and CCL5 in alcoholic hepatitis patients. We hypothesized that inhibition of CCL2 signaling with the dual CCR2/5 inhibitor, cenicriviroc (CVC), would attenuate ALD. In a mouse model of ALD, liver injury (ALT) and steatosis were prevented by CVC whether administered as “prevention” throughout the alcohol feeding or as “treatment” started after the development of ALD. Alcohol-induced increases in early liver fibrosis markers (Sirius-red, hydroxyproline and collagen-1) were normalized by both modes of CVC administration. We found that “prevention” and “treatment” with CVC reversed alcohol-related increases in liver mRNA and protein expression of TNFα, IL-1β, IL-6 and CCL2. CVC administration regimens prevented the increase in infiltrating MØ (F4/80lo CD11bhi) and reduced proinflammatory Ly6CHi MØ in livers of alcohol-fed mice. CVC increased liver T cell numbers and attenuated Il-2 expression without an effect on CD69+ or CD25+ T cell expression. In vitro, CVC inhibited CCL2-induced increases in hepatocyte Fasn and Adrp while it augmented Acox-1, Pgc1α and Ucp-2 expression, suggesting mechanisms for attenuated hepatocyte steatosis. We found that CCL2 and CCL5 sensitized hepatocytes to LPS-induced liver injury (TNFα, ALT and LDH release). Alcohol feeding induced apoptosis (PARP and caspase-3 cleavage) and pyroptosis (gasdermin D cleavage) in livers and CVC prevented both these forms of cell death. Together, our data demonstrate preclinical evidence for CCR2/CCR5 inhibition with CVC as a potent intervention to ameliorate alcohol-induced steatohepatitis and liver damage.
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影响因子：
4.2
作者：
Frazier, Thomas H;Stocker, Abigail M;McClain, Craig J
通讯作者：
McClain, Craig J
DOI：
10.1002/hep.29477
发表时间：
2018-05
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Friedman SL;Ratziu V;Harrison SA;Abdelmalek MF;Aithal GP;Caballeria J;Francque S;Farrell G;Kowdley KV;Craxi A;Simon K;Fischer L;Melchor-Khan L;Vest J;Wiens BL;Vig P;Seyedkazemi S;Goodman Z;Wong VW;Loomba R;Tacke F;Sanyal A;Lefebvre E
通讯作者：
Lefebvre E
趋化因子在调节慢性病毒感染过程中调节CD8 T细胞反应的作用。
影响因子：
6.7
作者：
Crawford A;Angelosanto JM;Nadwodny KL;Blackburn SD;Wherry EJ
通讯作者：
Wherry EJ
影响因子：
13.5
作者：
Bukong, Terence N.;Iracheta-Vellve, Arvin;Saha, Banishree;Ambade, Aditya;Satishchandran, Abhishek;Gyongyosi, Benedek;Lowe, Patrick;Catalano, Donna;Kodys, Karen;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi
DOI：
10.1084/jem.178.2.537
发表时间：
1993-08-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
López-Cabrera M;Santis AG;Fernández-Ruiz E;Blacher R;Esch F;Sánchez-Mateos P;Sánchez-Madrid F
通讯作者：
Sánchez-Madrid F