VEGF-A from Granuloma Macrophages Regulates Granulomatous Inflammation by a Non-angiogenic Pathway during Mycobacterial Infection

Harding, Jeffrey; Herbáth, Melinda; Chen, Yuli; Rayasam, Aditya; Ritter, Anna; Csóka, Balázs; Hasko, George; Michael, Iacovos P.; Fábry, Zsuzsanna; Nagy, András; Sándor, Mátyás

doi:10.1016/j.celrep.2019.04.072

Cited by 48 publications

(50 citation statements)

References 74 publications

(84 reference statements)

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“…In our model of dermal Leishmania infection, macrophages were the major VEGF-Aexpressing cell type in vivo. These results are consistent with granuloma macrophages being the major producers of VEGF-A during mycobacterial infection (42). We did not find elevated VEGF-A expression in the CD45 Ϫ cell fraction (which would contain fibroblasts), suggesting that fibroblasts and epidermal cells are not the dominant VEGF-A-producing cell type during infection, despite the ongoing wound healing response following L. major infection.…”

Section: Discussionsupporting

confidence: 89%

“…Similarly to Bartonella, the bacterium Clostridium difficile induces HIF-dependent VEGF-A production and vascular permeability to promote disease pathogenesis (53). Mycobacterium tuberculosis infection also induces VEGF-A production by macrophages, and the serum level of VEGF-A is elevated in tuberculosis patients (42,54). Importantly, VEGF-A production during Mycobacterium marinum infection in zebrafish promotes bacterial growth and dissemination (55).…”

Section: Discussionmentioning

confidence: 99%

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Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

et al. 2019

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Cutaneous leishmaniasis is characterized by vascular remodeling. Following infection with Leishmania parasites, the vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR-2) signaling pathway mediates lymphangiogenesis, which is critical for lesion resolution. Therefore, we investigated the cellular and molecular mediators involved in VEGF-A/VEGFR-2 signaling using a murine model of infection. We found that macrophages are the predominant cell type expressing VEGF-A during Leishmania major infection. Given that Leishmania parasites activate hypoxia-inducible factor 1α (HIF-1α) and this transcription factor can drive VEGF-A expression, we analyzed the expression of HIF-1α during infection. We showed that macrophages were also the major cell type expressing HIF-1α during infection and that infection-induced VEGF-A production is mediated by ARNT/HIF activation. Furthermore, mice deficient in myeloid ARNT/HIF signaling exhibited larger lesions without differences in parasite numbers. These data show that L. major infection induces macrophage VEGF-A production in an ARNT/HIF-dependent manner and suggest that ARNT/HIF signaling may limit inflammation by promoting VEGF-A production and, thus, lymphangiogenesis during infection.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

et al. 2019

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“…(Osherov and Ben-Ami 2016; Polena et al 2016; Oehlers et al 2015; Datta et al 2015) Mycobacterium-mediated angiogenic processes and granuloma vascularization result from the secretion of proangiogenic factors by the infected immune cells that compose the granuloma and play a complex and evolving role during the course of infection. (Torraca et al 2017; Polena et al 2016; Oehlers et al 2015; 2017) Extensive work has been conducted on understanding the role of angiogenesis in granuloma outcome, finding that inhibition of VEGF and other signaling pathways reduces pathogenicity and dissemination of infectious mycobacteria(Polena et al 2016; Oehlers et al 2015; Harding et al 2019) while normalizing surrounding vasculature, improving small molecule delivery, and decreasing hypoxia within the granuloma. (Datta et al 2015) Similarly, we observed increased secretion of VEGF from infected cells within our microscale granuloma model (Figure 3C), and therefore sought to illustrate one potential use of our platform as a complimentary tool for studies examining this infection-mediated process.…”

Section: Resultsmentioning

confidence: 99%

A modular microscale granuloma model for immune-microenvironment signaling studiesin vitro

Berry

Gower

et al. 2020

Preprint

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Tuberculosis (TB) is one of the most potent infectious diseases in the world, causing more deaths than any other single infectious agent. TB infection is caused by inhalation of Mycobacterium tuberculosis (Mtb) and subsequent phagocytosis and migration into the lung tissue by innate immune cells (e.g., alveolar macrophages, neutrophils, dendritic cells), resulting in the formation of a fused mass of immune cells known as the granuloma. Considered the pathological hallmark of TB, the granuloma is a complex microenvironment that is crucial for pathogen containment as well as pathogen survival. Disruption of the delicate granuloma microenvironment via numerous stimuli, such as variations in cytokine secretions, nutrient availability, and the makeup of immune cell population, can lead to an active infection. Herein, we present a novel in vitro model to examine the soluble factor signaling between a mycobacterial infection and its surrounding environment. Adapting a newly developed suspended microfluidic platform, known as Stacks, we established a modular microscale infection model containing human immune cells and a model mycobacterial strain that can easily integrate with different microenvironmental cues through simple spatial and temporal “stacking” of each module of the platform. We validate the establishment of suspended microscale (4 μL) infection cultures that secrete increased levels of proinflammatory factors IL-6, VEGF, and TNFα upon infection and form 3D aggregates (granuloma model) encapsulating the mycobacteria. As a proof of concept to demonstrate the capability of our platform to examine soluble factor signaling, we cocultured an in vitro angiogenesis model with the granuloma model and quantified morphology changes in endothelial structures as a result of culture conditions (P < 0.05 when comparing infected vs. uninfected coculture systems). We envision our modular in vitro granuloma model can be further expanded and adapted for studies focusing on the complex interplay between granulomatous structures and their surrounding microenvironment, as well as a complementary tool to augment in vivo signaling and mechanistic studies.

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“…Myeloid-derived VEGF-A was shown to regulate angiogenesis in mouse models of lung injury 59 and melanoma 20 . Alternatively, myeloid-derived VEGF-A was shown to control in ammation independently of vasculogenic effects in granulomatous in ammation 60 and in myocardial infarction 42 . A key question raised by our study is whether IL-1β and VEGF-A contributed to tumor progression in a sequential and stage-speci c manner, or in a synergic way.…”

Section: Discussionmentioning

confidence: 99%

Pro-atherogenic diet accelerates tumor growth in mice through IL-1β and myeloid cell-derived VEGF-A

Tran¹,

Esposito²,

Montabord³

et al. 2020

Preprint

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Aims: Myeloid inflammatory cells are recruited to the tumor microenvironment and subsequently educated in situ to acquire a pro-invasive, pro-angiogenic and immunosuppressive phenotype. Components of the metabolic syndrome are known to aggravate tumorigenesis in part through myeloid cell activation. We hypothesized that consumption of a high fat/high cholesterol pro-atherogenic diet and its associated low-grade inflammation would accelerate the initiation of solid tumors. Methods and results: Here, we show that two-week feeding of wildtype C57BL/6J mice with a pro-atherogenic diet increases the pool of circulating inflammatory Ly-6Chi monocytes available for initial melanoma development and amplifies the accumulation of myeloid cells within the tumor microenvironment, in an IL-1β-dependent manner. Under pro-atherogenic diet feeding, myeloid cells display heightened pro-angiogenic, pro-inflammatory and immunosuppressive activities. Within the first days after tumor implantation, myeloid cells become the main producer of VEGF-A in the tumor. Depletion of Ly-6Chi monocytes in mice fed with a pro-atherogenic diet limits immune cell infiltration in the tumor, and inhibits tumor growth. IL-1β deficiency or specific inhibition of VEGF-A in myeloid cells recapitulates the beneficial effect of Ly-6Chi monocyte depletion, suggesting their complementary roles in tumorigenesis in the context of mild hyperlipidemia. Conclusion: Our study shows that dyslipidemia provide high amounts of activated myeloid cells with pro-tumoral activity and shed light on cross-disease communication between cardiovascular pathologies and cancer. Translational Perspective: In this study we demonstrate that dyslipidemia accelerates the development of solid tumors through the increased infiltration of Ly6Chi monocytes that differentiate into pro-tumoral myeloid cells. These findings demonstrate that dyslipidemia can silently boost tumor development in normal-weight individuals through the action of IL-1β and VEGF-A. Our work sheds light on the potential benefit of targeting IL-1β and VEGF-A in cancer patients with moderate dyslipidemia.

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VEGF-A from Granuloma Macrophages Regulates Granulomatous Inflammation by a Non-angiogenic Pathway during Mycobacterial Infection

Cited by 48 publications

References 74 publications

Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

A modular microscale granuloma model for immune-microenvironment signaling studiesin vitro

Pro-atherogenic diet accelerates tumor growth in mice through IL-1β and myeloid cell-derived VEGF-A

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