Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo

Jetten, Nadine; Verbruggen, Sanne; Gijbels, Marion J.J.; Post, Mark J.; Winther, Menno P.J. de; Donners, Marjo M. P. C.

doi:10.1007/s10456-013-9381-6

Cited by 654 publications

(496 citation statements)

References 41 publications

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“…Activated macrophages, including M2-polarized macrophages, have been implicated in supporting angiogenesis and inflammation as multiple factors secreted by these cells exhibit pro-angiogenic activities (35,62). Although many studies indicate that synthetic RGD-containing peptides inhibit angiogenesis and tumor growth, our findings provide the first evidence that macrophages may generate and release an RGDKGE-containing collagen epitope that may exhibit pro-angiogenic activity.…”

Section: Discussionmentioning

confidence: 60%

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Ames

Contois

Caron

et al. 2016

Journal of Biological Chemistry

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Extracellular matrix (ECM) remodeling regulates angiogenesis. However, the precise mechanisms by which structural changes in ECM proteins contribute to angiogenesis are not fully understood. Integrins are molecules with the ability to detect compositional and structural changes within the ECM and integrate this information into a network of signaling circuits that coordinate context-dependent cell behavior. The role of integrin ␣v␤3 in angiogenesis is complex, as evidence exists for both positive and negative functions. The precise downstream signaling events initiated by ␣v␤3 may depend on the molecular characteristics of its ligands. Here, we identified an RGD-containing cryptic collagen epitope that is generated in vivo. Surprisingly, rather than inhibiting ␣v␤3 signaling, this collagen epitope promoted ␣v␤3 activation and stimulated angiogenesis and inflammation. An antibody directed to this RGDKGE epitope but not other RGD collagen epitopes inhibited angiogenesis and inflammation in vivo. The selective ability of this RGD epitope to promote angiogenesis and inflammation depends in part on its flanking KGE motif. Interestingly, a subset of macrophages may represent a physiologically relevant source of this collagen epitope. Here, we define an endothelial cell mechano-signaling pathway in which a cryptic collagen epitope activates ␣v␤3 leading to an Src and p38 MAPK-dependent cascade that leads to nuclear accumulation of Yes-associated protein (YAP) and stimulation of endothelial cell growth. Collectively, our findings not only provide evidence for a novel mechano-signaling pathway, but also define a possible therapeutic strategy to control ␣v␤3 signaling by targeting a proangiogenic and inflammatory ligand of ␣v␤3 rather than the receptor itself.

show abstract

Section: Discussionmentioning

confidence: 60%

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Ames

Contois

Caron

et al. 2016

Journal of Biological Chemistry

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“…Several reports indicate that TAMs perform multiple M2-associated functions including promotion of angiogenesis, matrix remodeling, and suppression of adaptive immunity. 13,41 These M2 macrophages have been already shown to promote angiogenesis in vivo, 42 which may be accelerated by the high VEGF seen in the livers of DEN C HF-HC-HSD mice.…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

et al. 2016

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Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat-high cholesterol-high sugar diet (HF-HC-HSD). We assessed liver MRI and histology, serum ALT, AFP, liver triglycerides, and cytokines. Macrophage polarization was determined by IL-12/TNFa (M1) and CD163/ CD206 (M2) expression using flow cytometry. Role of hif-1a-induced IL-10 was dissected in hepatocyte specific hif-1aKO and hif-1adPA (over-expression) mice. The western diet-induced features of NASH and accelerated HCC development after carcinogen exposure. Liver fibrosis and serum AFP were significantly increased in DEN C HF-HC-HSD mice compared to controls. Western diet resulted in macrophage (F4/ 80 C CD11b C ) infiltration to liver and DEN C HF-HC-HSD mice showed preferential increase in M2 macrophages. Isolated hepatocytes from western diet fed mice showed significant upregulation of the hypoxia-inducible transcription factor, hif-1a, and livers from hif-1a over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acid in vitro showed activation of hif-1a and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1a in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1a mediated IL-10 polarizing M2 macrophages.

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“…M1 macrophages are potent effector cells that kill microorganisms and tumors (46)(47)(48)(49). However, M2 macrophages play roles in regulating inflammation and adaptive immunity (50), promoting cell proliferation by producing growth factors (51), activating the arginase pathway (52) and angiogenesis (53), and scavenging debris by expressing scavenger receptors (54).…”

Section: Macrophagesmentioning

confidence: 99%

Yin-yang regulating effects of cancer-associated genes, proteins, and cells: An ancient Chinese concept in vogue in modern cancer research

Wei

2017

BST

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Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo

Cited by 654 publications

References 41 publications

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

Yin-yang regulating effects of cancer-associated genes, proteins, and cells: An ancient Chinese concept in vogue in modern cancer research

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