Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease

被引：77

作者：

Bala, Shashi ^{[1
]}

Csak, Timea ^{[1
]}

Kodys, Karen ^{[1
]}

Catalano, Donna ^{[1
]}

Ambade, Aditya ^{[1
]}

Furi, Istvan ^{[1
]}

Lowe, Patrick ^{[1
]}

Cho, Yeonhee ^{[1
]}

Iracheta-Vellve, Arvin ^{[1
]}

Szabo, Gyongyi ^{[1
]}

机构：

[1] Univ Massachusetts, Sch Med, Dept Med, 364 Plantat St, Worcester, MA 01605 USA

来源：

JOURNAL OF LEUKOCYTE BIOLOGY | 2017年 / 102卷 / 02期

基金：

美国国家卫生研究院;

关键词：

miR-155; IRAK-M; TNF-alpha; HDAC11; MyD88; TUMOR-ASSOCIATED MACROPHAGES; IRAK-M; HEPATIC STEATOSIS; INNATE IMMUNITY; ENDOTOXIN; MICRORNA-155; INFLAMMATION; POLARIZATION; EXPRESSION; TOLERANCE;

D O I：

10.1189/jlb.3A0716-310R

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Inflammation promotes the progression of alcoholic liver disease. Alcohol sensitizes KCs to gut-derived endotoxin (LPS); however, signaling pathways that perpetuate inflammation in alcoholic liver disease are only partially understood. We found that chronic alcohol feeding in mice induced miR-155, an inflammatory miRNA in isolated KCs. We hypothesized that miR-155 might increase the responsiveness of KCs to LPS via targeting the negative regulators of LPS signaling. Our results revealed that KCs that were isolated from alcohol-fed mice showed a decrease in IRAK-M, SHIP1, and PU. 1, and an increase in TNF-alpha levels. This was specific to KCs, as no significant differences were observed in these genes in hepatocytes. We found a causal effect of miR-155 deficiency on LPS responsiveness, as KCs that were isolated from miR-155 KO mice showed a greater induction of IRAK-M, SHIP1, and suppressor of cytokine signaling 1 after LPS treatment. C/EBP beta, a validated miR-155 target, stimulates IL-10 transcription. We found a higher induction of C/EBP beta and IL-10 in KCs that were isolated from miR-155 KO mice after LPS treatment. Gain-and loss-of-function studies affirmed that alcohol-induced miR-155 directly regulates IRAK-M, SHIP1, suppressor of cytokine signaling 1, and C/EBP beta, as miR-155 inhibition increased and miR-155 overexpression decreased these genes in LPS or alcohol-pretreated wildtype KCs. HDAC11, a regulator of IL-10, was significantly increased and IL-10 was decreased in KCs that were isolated from alcohol-fed mice. Functionally, knockdown of HDAC11 with small interfering RNA resulted in an IL-10 increase in LPS or alcohol-pretreated M phi. We found that acetaldehyde and NF-kappa B pathways regulate HDAC11 levels. Collectively, our results indicate that the alcohol-induced responsiveness of KCs to LPS, in part, is governed by miR-155 and HDAC11.

引用

页码：487 / 498

页数：12