Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization

Zhang, Jing; Muri, Jonathan; Fitzgerald, G. Kelley; Gorski, Tatiane; Gianni‐Barrera, Roberto; Masschelein, Evi; D’Hulst, Gommaar; Gilardoni, Paola; Turiel, Guillermo; Fan, Zheng; Wang, Tongtong; Planque, Mélanie; Carmeliet, Peter; Pellerin, Luc; Wolfrum, Christian; Fendt, Sarah-Maria; Banfi, Andrea; Stockmann, Christian; Soro-Arnáiz, Inés; Köpf, Manfred; Bock, Katrien De

doi:10.1016/j.cmet.2020.05.004

Cited by 305 publications

(246 citation statements)

References 81 publications

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“…It has been found that the energy metabolism of endothelial cells ECs is mainly dependent on glycolysis, and ECs-derived lactic acid can cause macrophages to be pola rized into M2-typ e. However, the loss of phosphofructokinase-2/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), the glycolytic regulator, reduces lactate secretion by ECs and inhibits M2-type macrophage. In addition, MCT1 knockout inhibits M2-type macrophage differentiation (69). This suggests that the production of lactic acid in the tumor microenvironment can promote M2-type differentiation of macrophages.…”

Section: The Polarization Of Macrophages By Stromal Cellular Compartmmentioning

confidence: 98%

The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy

2020

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Tumor microenvironment (TME) is composed of tumor cells and surrounding non-tumor stromal cells, mainly including tumor associated macrophages (TAMs), endothelial cells, and carcinoma-associated fibroblasts (CAFs). The TAMs are the major components of non-tumor stromal cells, and play an important role in promoting the occurrence and development of tumors. Macrophages originate from bone marrow hematopoietic stem cells and embryonic yolk sacs. There is close crosstalk between TAMs and tumor cells. With the occurrence of tumors, tumor cells secrete various chemokines to recruit monocytes to infiltrate tumor tissues and further promote their M2-type polarization. Importantly, M2-like TAMs can in turn accelerate tumor growth, promote tumor cell invasion and metastasis, and inhibit immune killing to promote tumor progression. Therefore, targeting TAMs in tumor tissues has become one of the principal strategies in current tumor immunotherapy. Current treatment strategies focus on reducing macrophage infiltration in tumor tissues and reprogramming TAMs to M1like to kill tumors. Although these treatments have had some success, their effects are still limited. This paper mainly summarized the recruitment and polarization of macrophages by tumors, the support of TAMs for the growth of tumors, and the research progress of TAMs targeting tumors, to provide new treatment strategies for tumor immunotherapy.

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Section: The Polarization Of Macrophages By Stromal Cellular Compartmmentioning

confidence: 98%

The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy

2020

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“…Charts combine data from eight sections per animal, three images per section (4,5 animals per group, saline controls are combined); statistical significance was assessed by one-way ANOVA with Dunnett's Multiple Comparison Test, and *p < 0.05, **p < 0.01. myeloid cell marker (Mac 2, (Ho and Springer, 1982) to quantify inflammatory cell infiltration into lungs following epirubicin treatment ( Figure 7A). This is a critical parameter, as macrophage infiltration and activation status mediated vascular remodeling and organ microenvironment (Wenes et al, 2016;Zhang et al, 2020). The number of Mac2+ cells was systematically quantified using batch analyses and "particle analysis" function (ImageJ).…”

Section: Epirubicin Treatment Promotes Myeloid Cell Infiltration Intomentioning

confidence: 99%

Circulating Levels of Epirubicin Cause Endothelial Senescence While Compromising Metabolic Activity and Vascular Function

Eakin

Erlain

Burke

et al. 2020

Front. Cell Dev. Biol.

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Anthracycline-based chemotherapy is a common treatment for cancer patients. Because it is delivered intravenously, endothelial cells are exposed first and to the highest concentrations, prior to diffusion to target cells. Not surprisingly, vascular dysfunction is a consequence of anthracycline therapy. While chemotherapy-induced endothelial damage at administration sites has been investigated, the effects of lower doses encountered by distant microvascular networks has not. The aim of this study was to investigate the impact of epirubicin, a widely used anthracycline, on healthy endothelial cells to elucidate its effects on microvascular physiology. Here, endothelial cells were briefly exposed to low doses of epirubicin to recapitulate levels in circulation following dilution in the blood and compound half-life in circulation. Both immediate and prolonged responses to treatment were assessed to determine changes in endothelial function. Epirubicin caused a decrease in proliferation and viability in hUVEC, with lower doses resulting in a senescent phenotype in a large proportion of cells, accompanied by a significant increase in pro-inflammatory cytokines and a significant decrease in metabolic activity. Epirubicin exposure also impaired endothelial function with delayed wound closure, reduced angiogenic potential and increased monolayer permeability downstream of VE-cadherin internalization. Primary lung endothelial cells obtained from epirubicin-treated mice similarly demonstrated reduced viability and functional impairment. In vivo, epirubicin treatment resulted in persistent reduction in lung vascular density and significantly increased infiltration of myeloid cells. Modulation of endothelial status and inflammatory tissue microenvironment observed in response to low doses of epirubicin may predict risk for long-term secondary pathologies associated with chemotherapy.

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“…On the other hand, blocking the tyrosine kinase (TK) VEGF receptor 2 (VEGFR2) strongly interfered with both, the process of angiogenesis and arteriogenesis (Jazwa et al, 2016). In both types of vessel growth, VEGF is supplied by leukocytes, i.e., neutrophils and monocytes (Deindl et al, 2001;Scapini et al, 2004;Morrison et al, 2014;Lautz et al, 2018;Zhang et al, 2020). But in contrast to angiogenesis, in arteriogenesis, an amplified and sustained local activation of VEGFR2 is necessary to promote endothelial cell proliferation by high levels of ERK activation (Kofler and Simons, 2015).…”

Section: Introductionmentioning

confidence: 99%

RNase A Treatment Interferes With Leukocyte Recruitment, Neutrophil Extracellular Trap Formation, and Angiogenesis in Ischemic Muscle Tissue

et al. 2020

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Background: RNase A (the bovine equivalent to human RNase 1) and RNase 5 (angiogenin) are two closely related ribonucleases. RNase 5 is described as a powerful angiogenic factor. Whether RNase A shares the same angiogenic characteristic, or interferes with vessel growth as demonstrated for arteriogenesis, has never been investigated and is the topic of this present study. Methods and Results: To investigate whether RNase A shows a pro-or anti-angiogenic effect, we employed a murine hindlimb model, in which femoral artery ligation (FAL) results in arteriogenesis in the upper leg, and, due to provoked ischemia, in angiogenesis in the lower leg. C57BL/6J male mice underwent unilateral FAL, whereas the contralateral leg was sham operated. Two and seven days after the surgery and intravenous injection of RNase A (50 μg/kg dissolved in saline) or saline (control), the gastrocnemius muscles of mice were isolated from the lower legs for (immuno-) histological analyses. Hematoxylin and Eosin staining evidenced that RNase A treatment resulted in a higher degree of ischemic tissue damage. This was, however, associated with reduced angiogenesis, as evidenced by a reduced capillary/muscle fiber ratio. Moreover, RNase A treatment was associated with a significant reduction in leukocyte infiltration as shown by CD45 + (pan-leukocyte marker), Ly6G + or MPO + (neutrophils), MPO + /CitH 3 + [neutrophil extracellular traps (NETs)], and CD68 + (macrophages) staining. CD68/MRC1 double staining revealed that RNase A treated mice showed a reduced percentage of M1-like polarized (CD68 + /MRC1 −) macrophages whereas the percentage of M2-like polarized (CD68 + /MRC1 +) macrophages was increased. Conclusion: In contrast to RNase 5, RNase A interferes with angiogenesis, which is linked to reduced leukocyte infiltration and NET formation.

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Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization

Cited by 305 publications

References 81 publications

The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy

The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy

Circulating Levels of Epirubicin Cause Endothelial Senescence While Compromising Metabolic Activity and Vascular Function

RNase A Treatment Interferes With Leukocyte Recruitment, Neutrophil Extracellular Trap Formation, and Angiogenesis in Ischemic Muscle Tissue

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