The role of ATF4 in M2-polarised macrophage infiltration of infantile haemangioma

The biological role of macrophage infiltration into adipose tissue in obesity remains to be fully understood. We hypothesize that macrophages may act to stimulate angiogenesis in the adipose tissue. This possibility was examined by determining macrophage expression of angiogenic factor PDGF (platelet-derived growth factor) and regulation of tube formation of endothelial cells by PDGF. The data suggest that endothelial cell density was reduced in the adipose tissue of ob/ob mice. Expression of endothelial marker CD31 was decreased in protein and mRNA. The reduction was associated with an increase in macrophage infiltration. In the obese mice, PDGF concentration was elevated in the plasma, and its mRNA expression was increased in adipose tissue. Macrophages were found to be a major source of PDGF in adipose tissue, as deletion of macrophages led to a significant reduction in PDGF mRNA. In cell culture, PDGF expression was induced by hypoxia, and tube formation of endothelial cells was induced by PDGF. The PDGF activity was dependent on S6K, as inhibition of S6K in endothelial cells led to inhibition of the PDGF activity. We conclude that, in response to the reduced vascular density, macrophages may express PDGF in adipose tissue to facilitate capillary formation in obesity. Although the PDGF level is elevated in adipose tissue, its activity in angiogenesis is dependent on the availability of sufficient endothelial cells. The study suggests a new function of macrophages in the adipose tissue in obesity.

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RANKL Is Involved in Runx2-Triggered Hepatic Infiltration of Macrophages in Mice with NAFLD Induced by a High-Fat Diet

BioMed Research International ◽

10.1155/2020/6953421 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Li Zhong ◽

Jianghan Yuan ◽

Lu Huang ◽

Shan Li ◽

Liang Deng

Keyword(s):

High Fat Diet ◽

Macrophage Infiltration ◽

Macrophage Migration ◽

High Fat ◽

Transwell Assay ◽

Nonalcoholic Fatty Liver ◽

Related Transcription Factor

Background. Receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) is significant in the activation of inflammation. Runt-related transcription factor 2 (Runx2) promotes the hepatic infiltration of macrophages in nonalcoholic fatty liver disease (NAFLD). We studied how RANKL affects Runx2-triggered macrophage infiltration in NAFLD. Method. 30 male C57BL/6J mice at 4 weeks of age were utilized in this study, 20 mice received a high-fat diet (HFD), and 10 mice received standard rodent chow over 8 months. The histopathologic features of the liver were identified by H&E, Oil red O, and Masson staining. Runx2, RANKL, and F4/80 were analyzed by western blot, real-time PCR, and immunohistochemistry in vivo, respectively. Lentivirus or siRNA was utilized for transwell assay to investigate the role of RANKL in Runx2-induced macrophage migration in vitro. Results. Compared to controls, during NAFLD development, HFD increased Runx2 and RANKL in vivo in NASH (P<0.01). Meanwhile, a correlation between the expression of Runx2 and RANKL (P<0.05) was evident. In addition, the hepatic infiltration of macrophages was increased upon HFD feeding, and analysis showed that the macrophage infiltration was correlated with the expression of Runx2 or RANKL (P<0.05). In vitro, we found that overexpression or deficiency of Runx2 increased or decreased the production of RANKL in mHSCs. Then, transwell assay revealed that RANKL was involved in Runx2-induced macrophage migration. Conclusions. Overall, RANKL is involved in Runx2-triggered macrophage migration during NAFLD pathogenesis, which may provide an underlying therapeutic target for NAFLD.

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Isoform-Specific Roles of ERK1 and ERK2 in Arteriogenesis

Cells ◽

10.3390/cells9010038 ◽

2019 ◽

Vol 9 (1) ◽

pp. 38 ◽

Cited By ~ 6

Author(s):

Nicolas Ricard ◽

Jiasheng Zhang ◽

Zhen W. Zhuang ◽

Michael Simons

Keyword(s):

Endothelial Cells ◽

Intracellular Signaling ◽

Clinical Importance ◽

Macrophage Infiltration ◽

Endothelial Cell Proliferation ◽

Vascular Endothelial ◽

Ischemic Event ◽

Intracellular Signaling Pathway ◽

First Time

Despite the clinical importance of arteriogenesis, this biological process is poorly understood. ERK1 and ERK2 are key components of a major intracellular signaling pathway activated by vascular endothelial growth (VEGF) and FGF2, growth factors critical to arteriogenesis. To investigate the specific role of each ERK isoform in arteriogenesis, we used mice with a global Erk1 knockout as well as Erk1 and Erk2 floxed mice to delete Erk1 or Erk2 in endothelial cells, macrophages, and smooth muscle cells. We found that ERK1 controls macrophage infiltration following an ischemic event. Loss of ERK1 in endothelial cells and macrophages induced an excessive macrophage infiltration leading to an increased but poorly functional arteriogenesis. Loss of ERK2 in endothelial cells leads to a decreased arteriogenesis due to decreased endothelial cell proliferation and a reduced eNOS expression. These findings show for the first time that isoform-specific roles of ERK1 and ERK2 in the control of arteriogenesis.

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Role of CX3CR1 signaling in malignant transformation of gliomas

Neuro-Oncology ◽

10.1093/neuonc/noaa075 ◽

2020 ◽

Vol 22 (10) ◽

pp. 1463-1473 ◽

Cited By ~ 2

Author(s):

Sungho Lee ◽

Khatri Latha ◽

Ganiraju Manyam ◽

Yuhui Yang ◽

Arvind Rao ◽

...

Keyword(s):

Tumor Microenvironment ◽

Mouse Model ◽

Malignant Transformation ◽

Microvessel Density ◽

Progression Free Survival ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

Low Grade ◽

Free Survival

Abstract Background Chemokine signaling may contribute to progression of low-grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3C chemokine receptor 1 (CX3CR1) signaling in malignant transformation of LGGs. Methods Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype-dependent alterations in survival, gene expression, and tumor microenvironment. A genetically engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3C ligand 1 (CX3CL1) and CX3CR1, individually or in combination. Results LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 vs 9.8 y, P < 0.05) and progression-free survival (8.6 vs 6.5 y, P < 0.05) compared with those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, coexpression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival. Conclusions CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.

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Role of nitric oxide in rat nephrotoxic nephritis: comparison between inducible and constitutive nitric oxide synthase.

Journal of the American Society of Nephrology ◽

10.1681/asn.v8111712 ◽

1997 ◽

Vol 8 (11) ◽

pp. 1712-1721 ◽

Cited By ~ 1

Author(s):

V Bremer ◽

A Tojo ◽

K Kimura ◽

Y Hirata ◽

A Goto ◽

...

Keyword(s):

Nitric Oxide ◽

Early Stage ◽

Renal Tissue ◽

Macrophage Infiltration ◽

Intercellular Adhesion Molecule ◽

No Production ◽

Sprague Dawley ◽

Nephrotoxic Nephritis ◽

Glomerular Damage

Nitric oxide (NO), generated by inducible NO synthase (iNOS) in migrating macrophages, is increased in glomerulonephritis. This study investigates the effect of NO inhibition on rat nephrotoxic nephritis (NTN) to clarify the role of NO production in glomerular damage. NTN was induced in Sprague Dawley rats by an injection of an anti-glomerular basement membrane (GBM) antibody. Urinary nitrite excretion and nitrite release from kidney slices (5.47 +/- 1.19 versus 2.15 +/- 0.73 nmol/mg protein, NTN versus Control, P < 0.05) were increased in NTN on day 2. Glomerular macrophage infiltration and intercellular adhesion molecule (ICAM)-1 expression increased from day 2. iNOS expression was increased in interstitial macrophages. Glomerular endothelial cell NOS (ecNOS) expression evaluated by counting immunogold particles along GBM was suppressed (0.06 +/- 0.02 versus 0.35 +/- 0.04 gold/micron GBM, P < 0.0001). Glomerular damage developed progressively. NG-nitro-L-arginine methyl ester (L-NAME), which inhibits both iNOS and ecNOS and aminoguanidine (AG), a relatively selective inhibitor for iNOS, equally suppressed nitrite in urine and renal tissue. Glomerular ICAM-1 expression and macrophage infiltration were reduced by L-NAME, but not by AG. Expression of ecNOS was significantly increased by L-NAME (0.91 +/- 0.08, P < 0.0001 versus NTN), but slightly by AG (0.18 +/- 0.04). AG significantly and L-NAME slightly attenuated the glomerular damage at day 4. In conclusion, suppression of iNOS prevents glomerular damage in the early stage of NTN. Treatment by L-NAME reduces macrophage infiltration by suppression of ICAM-1 expression, which may be explained by an increase in ecNOS expression.

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Role of ATF3 as a prognostic biomarker and correlation of ATF3 expression with macrophage infiltration in hepatocellular carcinoma

10.21203/rs.3.rs-60577/v2 ◽

2020 ◽

Author(s):

Lijuan Li ◽

Shaohua Song ◽

Xuailin Fang ◽

Donglin Cao

Keyword(s):

Hepatocellular Carcinoma ◽

Transcription Factors ◽

Regulatory Networks ◽

Macrophage Infiltration ◽

Future Research ◽

Activating Transcription Factor 3 ◽

Poor Overall Survival ◽

Basic Leucine Zipper ◽

Atf3 Expression

Abstract Background: The abnormal expression of activating transcription factor 3 (ATF3), a member of the basic leucine zipper (bZIP) family of transcription factors, is associated with carcinogenesis. However, the expression pattern and exact role of ATF3 in the development and progression of hepatocellular carcinoma (HCC) remain unclear. Methods: We used UALCAN, ONCOMINE, Kaplan-Meier plotter, and cBioPortal databases to investigate the prognostic value of ATF3 expression in HCC. Results: ATF3 was found to be expressed at low levels in multiple HCC tumor tissues. Moreover, low ATF3 expression was significantly associated with clinical cancer stage and pathological tumor grade in patients with HCC. Therefore, low expression of ATF3 was significantly associated with poor overall survival in patients with HCC. Functional network analysis showed that ATF3 regulates cytokine receptors and signaling pathways via various cancer-related kinases, miRNAs, and transcription factors. ATF3 expression was found to be correlated with macrophage infiltration levels and with macrophage immune marker sets in HCC patients. Conclusions: Using data mining methods, we clarified the role of ATF3 expression and related regulatory networks in HCC, laying a foundation for further functional research. Future research will validate our findings and establish clinical applications of ATF3 in the diagnosis and treatment of HCC.

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(Pro)renin receptor promotes crescent formation via the ERK1/2 and Wnt/β-catenin pathways in glomerulonephritis

AJP Renal Physiology ◽

10.1152/ajprenal.00250.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. F571-F578

Author(s):

Maki Urushihara ◽

Shuji Kondo ◽

Yukiko Kinoshita ◽

Natsuko Ozaki ◽

Ariunbold Jamba ◽

...

Keyword(s):

Cell Proliferation ◽

Basement Membrane ◽

Glomerular Basement Membrane ◽

Mesangial Cells ◽

Macrophage Infiltration ◽

Crescent Formation ◽

Sirna Treatment ◽

Extracellular Signal ◽

Parietal Epithelial Cells

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active β-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active β-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the β-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/β-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.

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