Interleukin-18 Amplifies Macrophage Polarization and Morphological Alteration, Leading to Excessive Angiogenesis

M2 macrophage (Mφ) promotes pathologic angiogenesis through a release of pro-angiogenic mediators or the direct cell–cell interaction with endothelium in the micromilieu of several chronic inflammatory diseases, including rheumatoid arthritis and cancer, where interleukin (IL)-18 also contributes to excessive angiogenesis. However, the detailed mechanism remains unclear. The aim of this study is to investigate the mechanism by which M2 Mφs in the micromilieu containing IL-18 induce excessive angiogenesis in the in vitro experimental model using mouse Mφ-like cell line, RAW264.7 cells, and mouse endothelial cell line, b.End5 cells. We discovered that IL-18 acts synergistically with IL-10 to amplify the production of Mφ-derived mediators like osteopontin (OPN) and thrombin, yielding thrombin-cleaved form of OPN generation, which acts through integrins α4/α9, thereby augmenting M2 polarization of Mφ with characteristics of increasing surface CD163 expression in association with morphological alteration. Furthermore, the results of visualizing temporal behavior and morphological alteration of Mφs during angiogenesis demonstrated that M2-like Mφs induced excessive angiogenesis through the direct cell–cell interaction with endothelial cells, possibly mediated by CD163.

• Publication year

  2018

• Venue

  Frontiers in Immunology

• Publication date

  2018-03-06

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.3389/fimmu.2018.00334PMID 29559970PMCID 5845536
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Macrophage plasticity, polarization, and function in health and disease

  2018cited by this paper
• Elevated serum interleukin-10 level and M2 macrophage infiltration are associated with poor survival in angioimmunoblastic T-cell lymphoma

  2017cited by this paper
• Tenascin-C and Integrin α9 Mediate Interactions of Prostate Cancer with the Bone Microenvironment.

  2017cited by this paper
• The role of innate immune cells in tissue inflammation in spondyloarthritis

  2017cited by this paper
• PI3Kγ Activates Integrin α4 and Promotes Immune Suppressive Myeloid Cell Polarization during Tumor Progression

  2017cited by this paper
• Non-classical monocytes are biased progenitors of wound healing macrophages during soft tissue injury

  2017cited by this paper
• Osteopontin affects macrophage polarization promoting endocytic but not inflammatory properties

  2016cited by this paper
• miR‐126‐3p Promotes Matrix‐Dependent Perivascular Cell Attachment, Migration and Intercellular Interaction

  2016cited by this paper
• Tumor-associated macrophages and anti-tumor therapies: complex links

  2016cited by this paper
• Macrophage colony-stimulating factor expressed in non-cancer tissues provides predictive powers for recurrence in hepatocellular carcinoma

  2016influential reference
• Interleukin 18 promotes myofibroblast activation of valvular interstitial cells.

  2016cited by this paper
• Biomarkers for evaluation of treatment response in classical Hodgkin lymphoma: comparison of sGalectin‐1, sCD163 and sCD30 with TARC

  2016cited by this paper
• The increase of circulating PD-L1-expressing CD68+ macrophage in ovarian cancer

  2016cited by this paper
• 9A.03: OSTEOPONTIN AND OSTEOPROTEGERIN ACTIVATE MONOCYTES INTO ANTI-INFLAMMATORY PROPERTIES IN THE PATIENTS WITH HYPERTENSION-RELATED VASCULAR CALCIFICATION

  2015cited by this paper
• The significance of the co-existence of osteopontin and tumor-associated macrophages in gastric cancer progression

  2015cited by this paper
• Osteopontin is proteolytically processed by matrix metalloproteinase 9.

  2015cited by this paper
• M2-polarized macrophages in keratocystic odontogenic tumor: relation to tumor angiogenesis

  2015cited by this paper
• IL-18 contributes to susceptibility to Leishmania amazonensis infection by macrophage-independent mechanisms.

  2015cited by this paper
• Molecular features of macrophage activation.

  2015cited by this paper
• Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination

  2015cited by this paper
• Decrease of CD68 Synovial Macrophages in Celastrol Treated Arthritic Rats

  2015cited by this paper
• The M1 and M2 paradigm of macrophage activation: time for reassessment

  2014cited by this paper
• Osteopontin as a therapeutic target for cancer

  2014influential reference
• Monocyte/macrophage‐derived soluble CD163: a novel biomarker in multiple myeloma

  2014cited by this paper
• Osteopontin signaling upregulates cyclooxygenase-2 expression in tumor-associated macrophages leading to enhanced angiogenesis and melanoma growth via α9β1 integrin

  2014cited by this paper
• α9β1 integrin acts as a critical intrinsic regulator of human rheumatoid arthritis.

  2014cited by this paper
• A Novel Cryptic Binding Motif, LRSKSRSFQVSDEQY, in the C-Terminal Fragment of MMP-3/7-Cleaved Osteopontin as a Novel Ligand for α9β1 Integrin Is Involved in the Anti-Type II Collagen Antibody-Induced Arthritis

  2014cited by this paper
• The role of macrophage phenotype in vascularization of tissue engineering scaffolds.

  2014cited by this paper
• TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

  2014cited by this paper
• Monocytes and macrophages: developmental pathways and tissue homeostasis

  2014cited by this paper
• Macrophage activation and polarization: nomenclature and experimental guidelines.

  2014cited by this paper
• Cooperative Effects of FGF-2 and VEGF-A in Periodontal Ligament Cells

  2014cited by this paper
• Enhancement of phagocytosis and cytotoxicity in macrophages by tumor-derived IL-18 stimulation

  2014cited by this paper
• CD163 Expression Was Associated with Angiogenesis and Shortened Survival in Patients with Uniformly Treated Classical Hodgkin Lymphoma

  2014cited by this paper
• Doxycycline Inhibits Polarization of Macrophages to the Proangiogenic M2-type and Subsequent Neovascularization*

  2014cited by this paper
• Osteopontin signaling upregulates cyclooxygenase-2 expression in tumor-associated macrophages leading to enhanced angiogenesis and melanoma growth via α9β1 integrin

  2014cited by this paper
• Molecular Mechanisms That Influence the Macrophage M1–M2 Polarization Balance

  2014cited by this paper
• CD163 and Inflammation: Biological, Diagnostic, and Therapeutic Aspects

  2013cited by this paper
• Macrophage plasticity and polarization in tissue repair and remodelling

  2013cited by this paper
• Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9.

  2013cited by this paper
• Interleukin 18: friend or foe in cancer.

  2013cited by this paper
• Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo

  2013cited by this paper
• Interaction of Osteopontin with IL-18 in Obese Individuals: Implications for Insulin Resistance

  2013cited by this paper
• Clinical significance of CD163+ tumor‐associated macrophages in patients with adult T‐cell leukemia/lymphoma

  2013cited by this paper
• Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage*

  2012cited by this paper
• Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma

  2011cited by this paper
• Osteopontin in macrophage function

  2011cited by this paper
• Macrophage regulation of tumor angiogenesis: implications for cancer therapy.

  2011cited by this paper
• Osteopontin, intrinsic tissue regulator of intractable inflammatory diseases

  2011cited by this paper
• Interleukin-18: A Mediator of Inflammation and Angiogenesis in Rheumatoid Arthritis

  2011cited by this paper
• Role of thrombin as a tumor growth factor

  2010cited by this paper
• Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction.

  2010cited by this paper
• Osteopontin Is Cleaved at Multiple Sites Close to Its Integrin-binding Motifs in Milk and Is a Novel Substrate for Plasmin and Cathepsin D*

  2010cited by this paper
• Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases

  2010cited by this paper
• Disease-associated functions of IL-33: the new kid in the IL-1 family

  2010cited by this paper
• Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma

  2010cited by this paper
• New insights in synovial angiogenesis.

  2010influential reference
• Macrophage diversity enhances tumor progression and metastasis.

  2010cited by this paper
• M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis

  2009cited by this paper
• Thrombin-Cleaved Osteopontin in Synovial Fluid of Subjects with Rheumatoid Arthritis

  2009cited by this paper
• Induction of angiogenesis by murine resistin: putative role of PI3-kinase and NO-dependent pathways.

  2009cited by this paper
• α9 Integrin and Its Ligands Constitute Critical Joint Microenvironments for Development of Autoimmune Arthritis1

  2009cited by this paper
• Thrombin induces tumor cell cycle activation and spontaneous growth by down-regulation of p27Kip1, in association with the up-regulation of Skp2 and MiR-222.

  2009cited by this paper
• IL‐1, IL‐18, and IL‐33 families of cytokines

  2008cited by this paper
• Coagulation, anticoagulation and pancreatic carcinoma

  2008cited by this paper
• IL-18 induces a marked gene expression profile change and increased Ccl1 (I-309) production in mouse mucosal mast cell homologs.

  2008cited by this paper
• Cells of the synovium in rheumatoid arthritis. Macrophages

  2007cited by this paper
• Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed?

  2007cited by this paper
• Macrophages and their products in rheumatoid arthritis

  2007cited by this paper
• Cells of the synovium in rheumatoid arthritis. B cells

  2007cited by this paper
• Murine macrophage P2X7 receptors support rapid prothrombotic responses.

  2007cited by this paper
• Ovarian Cancer Cells Polarize Macrophages Toward A Tumor-Associated Phenotype1

  2006cited by this paper
• Interleukin-10 and Th2 Cytokines Differentially Regulate Osteopontin Expression in Human Monocytes and Dendritic Cells

  2006cited by this paper
• The Crucial Role of Cyclooxygenase-2 in Osteopontin-Induced Protein Kinase C α/c-Src/IκB Kinase α/β–Dependent Prostate Tumor Progression and Angiogenesis

  2006cited by this paper
• Crosstalk between thrombosis and inflammation in lung reperfusion injury.

  2006cited by this paper
• Osteopontin: role in cell signaling and cancer progression.

  2006cited by this paper
• Potential role of microglia in retinal blood vessel formation.

  2006cited by this paper
• The crucial role of cyclooxygenase-2 in osteopontin-induced protein kinase C alpha/c-Src/IkappaB kinase alpha/beta-dependent prostate tumor progression and angiogenesis.

  2006cited by this paper
• Role of osteopontin in amplification and perpetuation of rheumatoid synovitis.

  2005cited by this paper
• Effects of oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid arthritis.

  2004cited by this paper
• Matrix metalloproteinases as modulators of inflammation and innate immunity

  2004cited by this paper
• Interleukin-18 promotes joint inflammation and induces interleukin-1-driven cartilage destruction.

  2004cited by this paper
• Local expression of matrix metalloproteinases, cathepsins, and their inhibitors during the development of murine antigen-induced arthritis

  2004cited by this paper
• Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis

  2004cited by this paper
• Implications for Cancer Therapy

  2003cited by this paper
• Association of interleukin-18 expression with enhanced levels of both interleukin-1beta and tumor necrosis factor alpha in knee synovial tissue of patients with rheumatoid arthritis.

  2003cited by this paper
• VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization

  2003cited by this paper
• Macrophage depletion inhibits experimental choroidal neovascularization.

  2003cited by this paper
• Alpha 4 integrin antagonists.

  2002cited by this paper
• Extravascular coagulation and the plasminogen activator/plasmin system in rheumatoid arthritis.

  2002cited by this paper
• Macrophage subpopulations in rheumatoid synovium: reduced CD163 expression in CD4+ T lymphocyte-rich microenvironments.

  2002cited by this paper
• Elevated levels of soluble CD163 in sera and fluids from rheumatoid arthritis patients and inhibition of the shedding of CD163 by TIMP‐3

  2002cited by this paper
• Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice

  2002cited by this paper
• Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy

  2001cited by this paper
• Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis.

  2001cited by this paper
• Osteopontin Is a Negative Feedback Regulator of Nitric Oxide Synthesis in Murine Macrophages1

  2001cited by this paper
• Amelioration of collagen-induced arthritis by thrombin inhibition.

  2001cited by this paper
• Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity.

  2000cited by this paper
• In vivo administration of IL‐18 can induce IgE production through Th2 cytokine induction and up‐regulation of CD40 ligand (CD154) expression on CD4+ T cells

  2000cited by this paper
• IL-18 is a potent coinducer of IL-13 in NK and T cells: a new potential role for IL-18 in modulating the immune response.

  1999cited by this paper

• IL-18 produced by pregnant uterus promotes essential inflammatory responses and fetoplacental growth.

  2026cites this paper
• LncRNA KCNQ1OT1 modulates M2 macrophage polarization and angiogenic signaling via the miR-142-3p/TRIM24 axis in retinal neovascularization.

  2026cites this paper
• The Cytotoxic Activity of Secondary Metabolites from Marine-Derived Penicillium spp.: A Review (2018–2024)

  2025cites this paper
• Mesenchymal stem cells and their exosomes: a novel approach to skin regeneration via signaling pathways activation

  2025cites this paper
• Unveiling the Phenotypic Variability of Macrophages: Insights from Donor Diversity and Pooling Strategies

  2025cites this paper
• The double-edged role of IL-18 in reproductive endocrine and reproductive immune related disorders.

  2025cites this paper
• The Role of AIM2 in Cancer Development: Inflammasomes and Beyond

  2025cites this paper
• Intentionally perforating the pulp chamber floor promotes M2 macrophage polarization in the dental pulp following tooth replantation in mice.

  2025cites this paper
• Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy

  2024cites this paper
• Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease

  2024cites this paper
• The effect of non‐contact electro capacitive cancer therapy on DMBA‐induced rat breast tumor angiogenesis

  2024cites this paper
• Galectin-3, Galectin-9, and Interleukin-18 Are Associated with Monocyte/Macrophage Activation and Turnover More so than Simian Immunodeficiency Virus-Associated Cardiac Pathology or Encephalitis

  2024cites this paper
• The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion to regulate the tumor immune microenvironment in pancreatic cancer

  2024cites this paper
• Basella alba L. (Malabar Spinach) as an Abundant Source of Betacyanins: Identification, Stability, and Bioactivity Studies on Natural and Processed Fruit Pigments

  2024cites this paper
• Agree to disagree: the contradiction between IL-18 and IL-37 reveals shared targets in cancer.

  2024cites this paper
• Novel Photo‐STING Agonists Delivered by Erythrocyte Efferocytosis‐Mimicking Pattern to Repolarize Tumor‐Associated Macrophages for Boosting Anticancer Immunotherapy

  2024cites this paper
• Advances in understanding the role of interleukins in pulmonary fibrosis (Review)

  2024cites this paper
• Establishment of a novel cytokine-related 8-gene signature for distinguishing and predicting the prognosis of triple-negative breast cancer

  2023cites this paper
• Macrophages heterogeneity and significance during human fetal pancreatic development

  2023cites this paper
• Macrophage-based therapy for intervertebral disc herniation: preclinical proof-of-concept

  2023cites this paper
• The central role of the NLRP3 inflammasome pathway in the pathogenesis of age-related diseases in the eye and the brain.

  2023cites this paper
• The marine Penicillium sp. GGF16-1-2 metabolite dicitrinone G inhibits pancreatic angiogenesis by regulating the activation of NLRP3 inflammasome

  2023cites this paper
• The Notch signaling-regulated angiogenesis in rheumatoid arthritis: pathogenic mechanisms and therapeutic potentials

  2023cites this paper
• The bone mesenchymal stem cell-derived exosomal miR-146a-5p promotes diabetic wound healing in mice via macrophage M1/M2 polarization.

  2023cites this paper
• Angiogenesis related genes in Takayasu Arteritis (TAK): robust association with Tag SNPs of IL-18 and FGF-2 in a South Asian Cohort

  2023cites this paper
• Global scientific trends update on macrophage polarization in rheumatoid arthritis: A bibliometric and visualized analysis from 2000 to 2022

  2023cites this paper
• Melatonin-pretreated human umbilical cord mesenchymal stem cells improved endometrium regeneration and fertility recovery through macrophage immunomodulation in rats with intrauterine adhesions

  2023cites this paper
• Ebi3 knockout aggravates experimental periodontitis via Th17 polarization.

  2023cites this paper
• Manipulation of the crosstalk between tumor angiogenesis and immunosuppression in the tumor microenvironment: Insight into the combination therapy of anti-angiogenesis and immune checkpoint blockade

  2022cites this paper
• The Good, the Bad, and the Ugly: Neutrophils, Angiogenesis, and Cancer

  2022cites this paper
• Identification of Diagnostic Biomarkers, Immune Infiltration Characteristics, and Potential Compounds in Rheumatoid Arthritis

  2022cites this paper
• Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine

  2022cites this paper
• Insights into inflammasome regulation: cellular, molecular, and pathogenic control of inflammasome activation

  2022cites this paper
• Osteopontin in Cancer: Mechanisms and Therapeutic Targets

  2022cites this paper
• MRTF may be the missing link in a multiscale mechanobiology approach toward macrophage dysfunction in space

  2022influential citation
• [IFN-γ and IL-12 from Concentrated Ascites in Patients with Pancreatic Cancer Exerts Growth Inhibitory Effects against Pancreatic Cancer Cells].

  2022cites this paper
• The Association of uPA, uPAR, and suPAR System with Inflammation and Joint Damage in Rheumatoid Arthritis: suPAR as a Biomarker in the Light of a Personalized Medicine Perspective

  2022cites this paper
• Macrophage response mediated by extracellular matrix: recent progress

  2022cites this paper
• Macrophage Polarization in Skin Wound Healing: Progress in Biology and Therapeutics

  2021cites this paper
• Prolonged oral ingestion of microplastics induced inflammation in the liver tissues of C57BL/6J mice through polarization of macrophages and increased infiltration of natural killer cells.

  2021cites this paper
• CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells

  2021cites this paper
• Contribution of Ezrin on the Cell Surface Plasma Membrane Localization of Programmed Cell Death Ligand-1 in Human Choriocarcinoma JEG-3 Cells

  2021cites this paper
• Involvement of multiple scavenger receptors in advanced glycation end product-induced vessel tube formation in endothelial cells.

  2021cites this paper
• Inflammation in Metabolic Cardiomyopathy

  2021cites this paper
• Ezrin Modulates the Cell Surface Expression of Programmed Cell Death Ligand-1 in Human Cervical Adenocarcinoma Cells

  2021cites this paper
• Role of Ezrin/Radixin/Moesin in the Surface Localization of Programmed Cell Death Ligand-1 in Human Colon Adenocarcinoma LS180 Cells

  2021cites this paper
• New Angiogenic Regulators Produced by TAMs: Perspective for Targeting Tumor Angiogenesis

  2021cites this paper
• Subcellular distribution of ezrin/radixin/moesin and their roles in the cell surface localization and transport function of P-glycoprotein in human colon adenocarcinoma LS180 cells

  2021cites this paper
• Cytotoxic T cells response with decreased CD4/CD8 ratio during mammary tumors inhibition in rats induced by non-contact electric fields

  2021cites this paper
• Macrophage Polarization in Skin Wound Healing: Progress in Biology and Therapeutics

  2021cites this paper
• Sex disparities in influenza: A multiscale network analysis

  2021cites this paper
• IL-18 and Lower Risk for Lung Cancer: Triangulated Evidence from Germline Predictions, Pre-Diagnostic Measurements, and Tumor Expression

  2021cites this paper
• Oxidative stress and macrophage infiltration in IgA nephropathy

  2021cites this paper
• Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway

  2020cites this paper
• Macrophage-expressed CD51 promotes cancer stem cell properties via the TGF-β1/smad2/3 axis in pancreatic cancer.

  2019cites this paper
• Cell wall mannoprotein of Candida albicans polarizes macrophages and affects proliferation and apoptosis through activation of the Akt signal pathway.

  2019cites this paper
• CCL2 and IL18 expressions may associate with the anti-proliferative effect of noncontact electro capacitive cancer therapy in vivo

  2019cites this paper
• Neurochemical and neuroinflammatory perturbations in two Gulf War Illness models: modulation by the immunotherapeutic LNFPIII.

  2019cites this paper
• Role of Matrix Metalloproteinases in Angiogenesis and Cancer

  2019cites this paper
• The role of interleukin-18 in pancreatitis and pancreatic cancer.

  2019cites this paper
• IL-1 Family Cytokine Regulation of Vascular Permeability and Angiogenesis

  2019cites this paper
• CCL2 and IL18 expressions may associate with the anti-proliferative effect of noncontact electro capacitive cancer therapy in vivo.

  2019cites this paper
• Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

  2018cites this paper
• Peroxisome proliferator–activated receptor γ (PPARγ) induces the gene expression of integrin αVβ5 to promote macrophage M2 polarization

  2018cites this paper
• Implications of Angiogenesis Involvement in Arthritis

  2018influential citation
• uPA/uPAR signaling in rheumatoid arthritis: Shedding light on its mechanism of action

  2018cites this paper