Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223

Calvente, Carolina Jiménez; Tameda, Masahiko; Johnson, Casey D.; Pilar, Hana del; Lin, Yun Chin; Adronikou, Nektaria; Jeu, Xavier de Mollerat du; Llorente, Cristina; Boyer, Josh; Feldstein, Ariel E.

doi:10.1172/jci122258

Cited by 185 publications

(180 citation statements)

References 58 publications

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“…This is in agreement with published studies demonstrating that neutrophil depletion by injection of Ly6G antibody markedly reduces chronic-binge ethanol feeding-induced liver injury and liver transplantation ischemia-reperfusion injury [8,38,39]. However, there are studies identifying the dual role for neutrophils in acetaminophen-induced acute liver injury, with neutrophil-mediated injury amplification early on, but exerting protective effects during the repair phase as depletion of neutrophils increases liver damage [40,41]. Also neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223 in CCl 4 -induced chronic liver injury [41].…”

Section: Discussionsupporting

confidence: 91%

“…However, there are studies identifying the dual role for neutrophils in acetaminophen-induced acute liver injury, with neutrophil-mediated injury amplification early on, but exerting protective effects during the repair phase as depletion of neutrophils increases liver damage [40,41]. Also neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223 in CCl 4 -induced chronic liver injury [41]. More studies will be needed to figure out the mechanism underlying differential role of neutrophils in different models of liver inflammation and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Neutrophil Chemotaxis and NETosis in Murine Chronic Liver Injury via Cannabinoid Receptor 1/Gαi/o/ROS/p38 MAPK Signaling Pathway

Zhou

Yang

Fan

et al. 2020

Cells

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Neutrophils play an essential role in the control of inflammatory diseases. However, whether cannabinoid receptors (CBs) play a role in neutrophil chemotaxis and NETosis in sterile liver inflammation remains unknown. The expression of marker genes on neutrophils was characterized by FACS, immunofluorescence, qRT-PCR, and Western blot. The amount of neutrophils was significantly elevated from 7 days and reached the peak at 2 weeks in carbon tetrachloride (CCl4)-treated mouse liver. The mRNA expression of neutrophil marker Ly6G had positive correlation with CB1 and CB2 expression in injured liver. In vitro CBs were abundantly expressed in isolated neutrophils and CB1 agonist ACEA promoted the chemotaxis and cytoskeletal remodeling, which can be suppressed by CB1 antagonist AM281. Moreover, ACEA induced NETosis, myeloperoxidase release from lysosome and ROS burst, indicating neutrophil activation, via Gαi/o. Conversely, CB2 agonist JWH133 had no effect on neutrophil function. ROS and p38 MAPK signaling pathways were involved in CB1-mediated neutrophil function, and ROS was upstream of p38 MAPK. CB1 blockade in vivo significantly attenuated neutrophil infiltration and liver inflammation in CCl4-treated mice. Taken together, CB1 mediates neutrophil chemotaxis and NETosis via Gαi/o/ROS/p38 MAPK signaling pathway in liver inflammation, which represents an effective therapeutic strategy for liver diseases.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Neutrophil Chemotaxis and NETosis in Murine Chronic Liver Injury via Cannabinoid Receptor 1/Gαi/o/ROS/p38 MAPK Signaling Pathway

Zhou

Yang

Fan

et al. 2020

Cells

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“…Aberrant hepatocyte death and persistent liver inflammation are recognized as drivers of liver fibrosis that in a chronic setting can promote HCC development (28). In the present study, we reported peripheral macrophage population accumulates during fibrosis.…”

Section: Discussionsupporting

confidence: 58%

miR-20a-5p/TGFBR2 Axis Affects Pro-inflammatory Macrophages and Aggravates Liver Fibrosis

Qie

et al. 2020

Front. Oncol.

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Combined inhibition of programmed death-ligand 1 (PD-L1) and transforming growth factor-β (TGF-β) displayed additive anti-tumor response in a subgroup of cancer patients, highlighting the importance of understanding the multifaceted roles of TGF-β in immunity and fibrosis. In the present research, we show that TGF-β signaling pathway, controlled by miR-20a-5p and transforming growth factor-β receptor 2 (TGFBR2), alters the inflammation and fibrosis processes in liver. We performed integrated analysis of differently expressed miRNA (DEM) associated with liver fibrosis and screened miR-20a-5p out as a key regulator in inflammation-driven liver fibrosis. We subsequently conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the genes targeted by miR-20a-5p. And the result showed that 12 target genes were significantly enriched in TGF-β signaling pathway. Further study showed that miR-20a-5p was down-regulated and involved in inflammation during liver fibrosis in human and mouse samples, indicating that miR-20a-5p and inflammation are functionally linked during liver fibrosis progression. To uncover the underlying pro-inflammatory mechanism of miR-20a-5p in liver fibrosis, we selected and verified TGFBR2, which is a key functional receptor in TGF-β signaling pathway, as a direct target gene of miR-20a-5p. The downregulation of miR-20a-5p in liver fibrosis resulted in TGFBR2-activated TGF-β signaling pathway, followed by the activation of macrophage and extracellular matrix (ECM) production by hepatic stellate cell (HSC). Our results identify the miR-20a-5p/TGFBR2 axis as a key regulator of TGF-β signaling, and highlight the critical role of miR-20a-5p in the development of liver fibrosis.

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“…We have recently demonstrated that microRNA-223 is a key rheostat that controls NLRP3 inflammasome activity in the liver. 77 We tested miR-223 3p, a synthetic analog sequence of endogenous miR-223, as a novel antiinflammatory approach for both acute and chronic liver injuries. 78 We evaluated the therapeutic effect of miR-223 3p in NASH induced by a 26-week feeding course of a highfat/cholesterol diet combined with fructose/sucrose-supplemented drinkable water (fat-fructose-cholesterol diet).…”

Section: Nlrp3-based Therapy For Ash and Nashmentioning

confidence: 99%

The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis

et al. 2020

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Nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis (ASH) are advanced forms of fatty liver diseases that are associated with a high morbidity and mortality worldwide. Patients with ASH or NASH are more susceptible to the progression of fibrosis and cirrhosis up to the development of hepatocellular carcinoma. Currently, there are limited medical therapies available. Accompanied by the asymptomatic disease progression, the demand for liver transplants is high. This review provides an overview about the growing evidence for a central role of NLR family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex that acts as a central driver of inflammation via activation of caspase 1, maturation and release of pro-inflammatory cytokines including interleukin-1β, and trigger of inflammatory pyroptotic cell death in both NASH and ASH. We also discuss potential therapeutic approaches targeting NLRP3 inflammasome and related upstream and downstream pathways to develop prognostic biomarkers and medical treatments for both liver diseases.

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Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223

Cited by 185 publications

References 58 publications

Neutrophil Chemotaxis and NETosis in Murine Chronic Liver Injury via Cannabinoid Receptor 1/Gαi/o/ROS/p38 MAPK Signaling Pathway

Neutrophil Chemotaxis and NETosis in Murine Chronic Liver Injury via Cannabinoid Receptor 1/Gαi/o/ROS/p38 MAPK Signaling Pathway

miR-20a-5p/TGFBR2 Axis Affects Pro-inflammatory Macrophages and Aggravates Liver Fibrosis

The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis

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