miRNAs Involved in M1/M2 Hyperpolarization Are Clustered and Coordinately Expressed in Alcoholic Hepatitis

Kim, Adam; Saikia, Paramananda; Nagy, Laura E.

doi:10.3389/fimmu.2019.01295

Cited by 27 publications

(30 citation statements)

References 46 publications

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“…M2-polarized macrophages express anti-inflammatory cytokines such as IL-10, thereby suppressing inflammation and promoting tissue healing [ 48 , 49 ]. Alcohol consumption increases expression of both M1 and M2 polarization in Kupffer cells (hyperpolarization) [ 50 ]. However, Kupffer cells from alcohol-fed animals are predominantly M1 phenotype which is associated with hepatic inflammation and tissue injury [ 47 , 50 , 51 , 52 ].…”

Section: Alcohol-associated Liver Diseasementioning

confidence: 99%

“…Alcohol consumption increases expression of both M1 and M2 polarization in Kupffer cells (hyperpolarization) [ 50 ]. However, Kupffer cells from alcohol-fed animals are predominantly M1 phenotype which is associated with hepatic inflammation and tissue injury [ 47 , 50 , 51 , 52 ]. In livers of patients who abuse alcohol, increased levels of both M1 and M2 Kupffer cells have been reported [ 53 ].…”

Section: Alcohol-associated Liver Diseasementioning

confidence: 99%

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cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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The importance of cyclic adenosine monophosphate (cAMP) in cellular responses to extracellular signals is well established. Many years after discovery, our understanding of the intricacy of cAMP signaling has improved dramatically. Multiple layers of regulation exist to ensure the specificity of cellular cAMP signaling. Hence, disturbances in cAMP homeostasis could arise at multiple levels, from changes in G protein coupled receptors and production of cAMP to the rate of degradation by phosphodiesterases. cAMP signaling plays critical roles in metabolism, inflammation and development of fibrosis in several tissues. Alcohol-associated liver disease (ALD) is a multifactorial condition ranging from a simple steatosis to steatohepatitis and fibrosis and ultimately cirrhosis, which might lead to hepatocellular cancer. To date, there is no FDA-approved therapy for ALD. Hence, identifying the targets for the treatment of ALD is an important undertaking. Several human studies have reported the changes in cAMP homeostasis in relation to alcohol use disorders. cAMP signaling has also been extensively studied in in vitro and in vivo models of ALD. This review focuses on the role of cAMP in the pathobiology of ALD with emphasis on the therapeutic potential of targeting cAMP signaling for the treatment of various stages of ALD.

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Section: Alcohol-associated Liver Diseasementioning

confidence: 99%

Section: Alcohol-associated Liver Diseasementioning

confidence: 99%

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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“…MiRNAs are powerful intracellular regulators involved in regulating the development, differentiation, and maturation of immune cells such as T cells, DCs, and macrophages 22 . Data from miRNA-sequencing and microarrays in M1, M2, and monocytes indicate that macrophage polarization is dynamically regulated by several miRNAs 11,23 . As an important family of miRNAs, let-7b-5p participates in the growth, proliferation, invasion, and metastasis of cancer by regulating the expression of a variety of oncogenes and cytokines 24 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of let-7b-5p contributes to anti-tumorigenic macrophage phenotype through SOCS1/STAT pathway in prostate cancer

Rong

et al. 2020

Preprint

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BackgroundDysfunction of microRNAs (miRNAs) is a major cause of aberrant expression of inflammatory cytokines and contributes to macrophage polarization. Previous studies have shown that miRNA let-7 is associated with cell differentiation, and the expression of let-7b-5p is significantly increased in M2 macrophages. However, the mechanism by which let-7b-5p regulates macrophage differentiation in prostate cancer (PCa) remains largely unknown.MethodsHuman macrophages were induced by the blood monocytes from healthy male donors. M1 macrophages were polarized by stimulating overnight with 100 ng/ml lipopolysaccharides and 100 ng/ml IFN-γ, while conditioned medium from PC-3 cells were used to induce prostatic macrophages (M-CMs) in vitro, and then let-7b-5p mimics or inhibitors were transfected into M1 and M-CMs for 72 hours respectively. The expression of cluster of differentiation 206 (CD206) in each group was detected by a High Throughput Connotation of Imaging System. Quantitative real-time polymerase chain reaction (qRT-PCR) was executed to examine the expression of inflammatory cytokines IL-10, IL-12, IL-13, TNF-alpha and let-7b in macrophages. SOCS1 protein level was evaluated by ELISA, and the phosphorylation difference of STAT family member proteins was analysized by CST signal pathway chip. Phagocytosis of macrophages and the effect of macrophages on the proliferation of prostate cancer cell PC-3 were evaluated by phagocytosis assay or Cell Counting Kit-8 (CCK-8). The relationship between SOCS1 and let-7b-5p was confirmed with the dual-luciferase reporter.ResultsThe expression of cluster of differentiation 206 (CD206), an M2-like macrophage surface molecule, was significantly increased in M1 macrophages treated with let-7b-5p mimics, while CD206 expression was decreased in M-CMs treated with let-7b-5p inhibitors. Overexpression or knockdown of let-7b-5p significantly affected the expression of inflammatory factors in macrophages including interleukin 10 (IL-10), IL-12, IL-13, and tumor necrosis factor alpha. Let-7b-5p downregulated the expression of suppressor of cytokine signaling 1 (SOCS1) and increased the phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5a proteins in M-CMs and M1 macrophages with let-7b-5p mimics compared with the other groups. In addition, with high expression of let-7b-5p, the phagocytosis of macrophages showed a significant decrease. As a result, M-CMs treated with let-7b-5p inhibitors reduced the proliferation of PC-3 PCa cells.ConclusionsCollectively, these data indicate that let-7b-5p may regulate M2 polarization through the SOCS1/STAT pathway, and reversal of M2 differentiation by let-7b-5p inhibitors can enhance macrophage phagocytosis, ultimately inhibiting the proliferation of PCa cells.Trial registrationNot applicable

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“…Relative messenger RNA (mRNA) expression was determined using gene‐specific primers (see Supporting Table ). Statistical analyses were performed on the ∆Ct values (average Ct of gene of interest – average Ct of 18S) …”

Section: Methodsmentioning

confidence: 99%

“…Statistical analyses were performed on the ∆Ct values (average Ct of gene of interest -average Ct of 18S). (21)…”

Section: Rna Isolation and Quantitative Real-time Polymerase Chain Rementioning

confidence: 99%

Nontranscriptional Activity of Interferon Regulatory Factor 3 Protects Mice From High‐Fat Diet‐Induced Liver Injury

Sanz‐Garcia¹,

McMullen²,

Chattopadhyay³

et al. 2019

Hepatol Commun

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Interferon regulatory factor 3 (IRF3) has both transcriptional and nontranscriptional functions. Transcriptional activity is dependent on serine phosphorylation of IRF3, while transcription‐independent IRF3‐mediated apoptosis requires ubiquitination. IRF3 also binds to inhibitor of nuclear factor kappa B kinase (IKKβ) in the cytosol, restricting nuclear translocation of p65. IRF3‐deficient mice are highly sensitive to high‐fat diet (HFD)‐induced liver injury; however, it is not known if transcriptional and/or nontranscriptional activity of IRF3 confers protection. Using a mouse model only expressing nontranscriptional functions of IRF3 (Irf3S1/S1), we tested the hypothesis that nontranscriptional activity of IRF3 protects mice from HFD‐induced liver injury. C57BL/6, Irf3−/−, and Irf3S1/S1 mice were fed an HFD for 12 weeks. In C57BL/6 mice, the HFD increased expression of interferon (IFN)‐dependent genes, despite a decrease in IRF3 protein in the liver. The HFD had no impact on IFN‐dependent gene expression Irf3−/− or Irf3S1/S1 mice, both lacking IRF3 transcriptional activity. Liver injury, apoptosis, and fibrosis were exacerbated in Irf3−/− compared to C57BL/6 mice following the HFD; this increase was ameliorated in Irf3S1/S1 mice. Similarly, expression of inflammatory cytokines as well as numbers of neutrophils and infiltrating monocytes was increased in Irf3−/− mice compared to C57BL/6 and Irf3S1/S1 mice. While the HFD increased the ubiquitination of IRF3, a response associated with IRF3‐mediated apoptosis, in Irf3S1/S1 mice, protection from liver injury was not due to differences in apoptosis of hepatocytes or immune cells. Instead, protection from HFD‐induced liver injury in Irf3S1/S1 mice was primarily associated with retardation of nuclear translocation of p65 and decreased expression of nuclear factor kappa B (NFκB)‐dependent inflammatory cytokines. Conclusion: Taken together, these data identify important contributions of the nontranscriptional function of IRF3, likely by reducing NFκB signaling, in dampening the hepatic inflammatory environment in response to an HFD.

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miRNAs Involved in M1/M2 Hyperpolarization Are Clustered and Coordinately Expressed in Alcoholic Hepatitis

Cited by 27 publications

References 46 publications

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

Inhibition of let-7b-5p contributes to anti-tumorigenic macrophage phenotype through SOCS1/STAT pathway in prostate cancer

Nontranscriptional Activity of Interferon Regulatory Factor 3 Protects Mice From High‐Fat Diet‐Induced Liver Injury

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