CD226 deletion improves post-infarction healing via modulating macrophage polarization in mice

Li, Jun; Song, Yun; Jin, Jingyi; Li, Guohua; Guo, Yongzheng; Yi, Huang; Zhang, Jinrui; Lu, Yajie; Zhang, Jinglong; Li, Cong-Ye; Gao, Chao; Lu, Yang; Fu, Feng; Chen, Fu-lin; Zhang, Shumiao; Jia, Min; Zheng, Guoxu; Chen, Lihua

doi:10.7150/thno.37106

Cited by 34 publications

(28 citation statements)

References 31 publications

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“…As tumour angiogenesis was associated with the progression and metastasis of HCC (G. B. Wang et al, 2010), we examined whether the in vivo repression of HCC tumour by geniposide was associated with angiogenesis inhibition. As shown in Figure 2c, the average intensity of positive CD31 (endothelial cell marker) or Ki67 (proliferation marker) signalling in hepatic tumour tissue was measured (J. Li et al, 2020). Spare CD31‐ or Ki67‐positive signals were detected in geniposide‐treated mice compared with that in control.…”

Section: Resultsmentioning

confidence: 99%

Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma

Zhang

Wang

Tan

et al. 2020

British J Pharmacology

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Background and Purpose: As a typical hypervascular tumour, hepatocellular carcinoma (HCC) is predominantly grown through angiogenesis. Geniposide is a promising anti-inflammatory compound found in Gardenia jasminoides, but its effects on the progression of HCC remain untested. Experimental Approach: The anti-HCC effects of geniposide was investigated in cellular models and orthotopic HCC mice. Transcriptional regulation of the VEGF promoter was measured by dual-luciferase reporter assay. The anti-angiogenic action of geniposide was measured by tube formation assay. Both surface plasmon resonance techniques and human phospho-kinase array analysis were utilized to validate the relationship between targets of geniposide and hepatocarcinogenesis. Key Results: Geniposide exhibited significant disruption of HCC proliferation, invasion, angiogenesis and lung metastasis in orthotopic HCC mice. Geniposide inhibited secretion of VEGF by HCC and suppressed the migration of endothelial cells and the formation of intra-tumour blood vessels, without cytotoxicity and independently of the transcription factor HIF-1α. Direct inhibition of TLR4 by geniposide led to the shutdown of the TLR4/MyD88 pathway and STAT3/Sp1-dependent VEGF production. However, LPS, an agonist of TLR4, restored STAT3/Sp1-related VEGF production in geniposide-inhibited HCC angiogenesis. Conclusion and Implications: The direct inhibitory effect of geniposide on TLR4/ MyD88 activation contributes to the suppression of STAT3/Sp1-dependent VEGF overexpression in HCC angiogenesis and pulmonary metastasis. This action of geniposide was not affected by stabilization of HIF-1α. Our study offers a novel anti-VEGF mechanism for the inhibition of HCC.

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Section: Resultsmentioning

confidence: 99%

Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma

Zhang

Wang

Tan

et al. 2020

British J Pharmacology

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“…Inhibition of DNAX accessory molecule 1 (DNAM-1), or CD226 receptor, is another strategy that can be utilized for the therapeutic activation of M2 following MI. CD226 expression on macrophages is highly increased in post-infarction heart tissue and CD226 knockout mice had better recovery after left anterior descending artery ligation [ 81 ]. Moreover, CD226 deletion tended to alleviate M2 macrophage polarization, while suppressing M1 type cells as well as creating a reparative healing microenvironment [ 81 ].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

“…CD226 expression on macrophages is highly increased in post-infarction heart tissue and CD226 knockout mice had better recovery after left anterior descending artery ligation [ 81 ]. Moreover, CD226 deletion tended to alleviate M2 macrophage polarization, while suppressing M1 type cells as well as creating a reparative healing microenvironment [ 81 ]. Angiotensin II (Ang II) can also be utilized to induce M2 phenotype in the infarcted hearts.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

“…This resulted in enhanced M2 polarization and improved cardiac repair in the mouse MI model [ 97 ]. In a study by Li and colleagues, knock-out of CD226, a receptor constitutively expressed on T cells, NK cells and monocytes, and involved in cell-mediated cytotoxicity, resulted in increased F4/80+ CD206+ M2 macrophages and decreased Mac-3+ iNOS+ M1 macrophages in mice with MI [ 81 ].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

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Macrophage Polarization in Cardiac Tissue Repair Following Myocardial Infarction

Kim

Nurakhayev

Nurkesh

et al. 2021

IJMS

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Cardiovascular disease is the leading cause of mortality and morbidity around the globe, creating a substantial socio-economic burden as a result. Myocardial infarction is a significant contributor to the detrimental impact of cardiovascular disease. The death of cardiomyocytes following myocardial infarction causes an immune response which leads to further destruction of tissue, and subsequently, results in the formation of non-contractile scar tissue. Macrophages have been recognized as important regulators and participants of inflammation and fibrosis following myocardial infarction. Macrophages are generally classified into two distinct groups, namely, classically activated, or M1 macrophages, and alternatively activated, or M2 macrophages. The phenotypic profile of cardiac macrophages, however, is much more diverse and should not be reduced to these two subsets. In this review, we describe the phenotypes and functions of macrophages which are present in the healthy, as well as the infarcted heart, and analyze them with respect to M1 and M2 polarization states. Furthermore, we discuss therapeutic strategies which utilize macrophage polarization towards an anti-inflammatory or reparative phenotype for the treatment of myocardial infarction.

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“…Macrophages, the most abundant innate immune cell type in normal lung tissue 4 , are characterized by their plasticity and diversity. Depending on the local microenvironment, macrophages manifest two distinctive phenotypes, the classically activated phenotype (M1) and the alternatively activated phenotype (M2) 5 . In general, M1 macrophages contribute to the host defense against pathogens by generating reactive nitric oxide (NO) via inducible nitric oxide synthase (iNOS) and releasing proinflammatory cytokines and chemokines such as IL-1β, IL-12, IL-23, CCL2 and TNF-α, while M2 macrophages have been shown to suppress inflammation and promote wound healing by producing cytokines and chemokines such as TGF-β, PDGF, CCL17 and CCL18 6 , 7 .…”

Section: Introductionmentioning

confidence: 99%

Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis

et al. 2021

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Idiopathic pulmonary fibrosis (IPF) is a chronic and diffuse form of interstitial lung disease of unknown etiology with a fatal outcome. Although various strategies for IPF have been developed over the last few decades, no significant positive impact on the prognosis of IPF has been observed. According to the current paradigm, macrophages have been recognized to play a significant role in IPF pathogenesis. Here, we report a potential nanomedicine-based gene therapy for IPF based on regulate macrophage polarization. Method: C57BL/6 mice were obtained and used to establish a bleomycin (BLM)-induced pulmonary fibrosis animal model, and Sart1 siRNA-loaded liposomes were designed for in vivo experiment. The experimental animals were administered BLM intratracheally on day 0 and treated with Sart1 siRNA on days 14 and 17. In the in vitro experiment, we further examined the function of Sart1 in macrophages. Results: Our data indicated that the liposomes could passively target the fibrotic area in the lung and efficiently accumulate in macrophages. The suppression of Sart1 by siRNA-loaded liposomes significantly protected mice against BLM-induced lung injury and fibrosis, which was attributed to attenuated M2 macrophage infiltration in the lung. Conclusion: Our study provides a valuable reference for modulating macrophage polarization and a promising strategy for the treatment of pulmonary fibrosis in clinical settings.

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CD226 deletion improves post-infarction healing via modulating macrophage polarization in mice

Cited by 34 publications

References 31 publications

Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma

Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma

Macrophage Polarization in Cardiac Tissue Repair Following Myocardial Infarction

Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis

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