456 M2 macrophage infiltration and Henoch-Schönlein’s purpura nephritis

Purpose. Myocardial regeneration is one of the most ambitious goals in prevention of adverse cardiac remodeling. Macrophages play a key role in transition from inflammatory to regenerative phase during wound healing following myocardial infarction (MI). We have accumulated data on macrophage properties ex vivo and in cell culture. However, there is no clear information about phenotypic heterogeneity of cardiac macrophages in patients with MI. The purpose of the project was to assess cardiac macrophage infiltration during wound healing following myocardial infarction in clinical settings taking into consideration experimental knowledge.Material and Methods. The study included 41 patients with fatal MI type 1. In addition to routine analysis, macrophages infiltration was assessed by immunohistochemistry. We used CD68 as a marker for the cells of the macrophage lineage, while CD163, CD206, and stabilin-1 were considered as M2 macrophage biomarkers. Nine patients who died from noncardiovascular causes comprised the control group.Results. The intensity of cardiac macrophage infiltration was higher during the regenerative phase than during the inflammatory phase. Results of immunohistochemical analysis demonstrated the presence of phenotypic heterogeneity of cardiac macrophages in patients with MI. We noticed that numbers of CD68+, CD163+, CD206+, and stabilin-1+ macrophages depended on MI phase.Conclusion. Our study supports prospects for implementation of macrophage phenotyping in clinic practice. Improved understanding of phenotypic heterogeneity might become the basis of a method to predict adverse cardiac remodeling and the first step in developing myocardial regeneration target therapy.

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FOXE1-Dependent Regulation of Macrophage Chemotaxis by Thyroid Cells In Vitro and In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms22147666 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7666

Author(s):

Sara C. Credendino ◽

Marta De Menna ◽

Irene Cantone ◽

Carmen Moccia ◽

Matteo Esposito ◽

...

Keyword(s):

Thyroid Cancer ◽

Immune Cells ◽

Cancer Susceptibility ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

Thyroid Cells ◽

Transcriptional Alterations ◽

Cancer Phenotypes

Forkhead box E1 (FOXE1) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer phenotypes. To identify relevant effectors playing roles in thyroid cancer development, here we analyse FOXE1-induced transcriptional alterations in thyroid cells that do not express endogenous FOXE1. Expression of FOXE1 elicits cell migration, while transcriptome analysis reveals that several immune cells-related categories are highly enriched in differentially expressed genes, including several upregulated chemokines involved in macrophage recruitment. Accordingly, FOXE1-expressing cells induce chemotaxis of co-cultured monocytes. We then asked if FOXE1 was able to regulate macrophage infiltration in thyroid cancers in vivo by using a mouse model of cancer, either wild type or with only one functional FOXE1 allele. Expression of the same set of chemokines directly correlates with FOXE1 dosage, and pro-tumourigenic M2 macrophage infiltration is decreased in tumours with reduced FOXE1. These data establish a novel link between FOXE1 and macrophages recruitment in the thyroid cancer microenvironment, highlighting an unsuspected function of this gene in the crosstalk between neoplastic and immune cells that shape tumour development and progression.

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Nucleolin Improves Heart Function During Recovery From Myocardial Infarction by Modulating Macrophage Polarization

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248421989570 ◽

2021 ◽

pp. 107424842198957

Author(s):

Yuting Tang ◽

Xiaofang Lin ◽

Cheng Chen ◽

Zhongyi Tong ◽

Hui Sun ◽

...

Keyword(s):

Myocardial Infarction ◽

Early Phase ◽

Heart Function ◽

Macrophage Polarization ◽

Late Phase ◽

Macrophage Infiltration ◽

Enzyme Linked Immunosorbent Assay ◽

M2 Macrophage ◽

M2 Macrophage Polarization ◽

Nucleolin Expression

Background: Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. Methods: Male BALB/c mice aged 6–8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. Results: Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. Conclusions: Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.

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Establishment and Validation of a Genetic Label Associated With M2 Macrophage Infiltration to Predict Survival in Colon Cancer Patients and Assist Immunotherapy

10.21203/rs.3.rs-712255/v1 ◽

2021 ◽

Author(s):

Boyang Xu ◽

Ziqi Peng ◽

Guanyu Yan ◽

Ningning Wang ◽

Moye Chen ◽

...

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Cancer Patients ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

High Morbidity ◽

M2 Macrophages ◽

Hub Genes

Abstract Background: Colon cancer is a kind of malignant tumor with high morbidity and mortality. Researchers have tried to interpret it from different perspectives and divide it into different subtypes in order to achieve individualized treatment. With the rise of immunotherapy, its value in the field of tumor has initially emerged. Based on the above background, from the perspective of immune infiltration, this study classified colon cancer according to the infiltration of M2 macrophages in patients with colon cancer and further explored it.Methods: Cibersort was used to analyze the level of immune cell infiltration in colon cancer patients in the TCGA database. WGCNA, Consensus Clustering analysis, Lasso analysis, and univariate KM analysis were used to screen and verify the hub genes associated with M2 macrophages. PCA was used to establish the M2 macrophage-related score—M2I Score. The correlation between M2I Score and somatic cell variation and microsatellite instability were analysed. Furthermore the correlation between M2 macrophage score and differences in immunotherapy sensitivity was also explored. Results: M2 macrophage infiltration was associated with poor prognosis. Four hub genes (ANKS4B, CTSD, TIMP1, and ZNF703) were selected as the progression-related genes associated with M2 macrophages. A stable and accurate M2I Score for M2 macrophages used in COAD was constructed based on four hub genes. M2I Score was positively correlated with tumor mutation load (TMB). The M2I Score of MSI-H group was higher than that of MSI-L group and MSS group. Combine with the TCIA database, we concluded that patients with a high M2I Score were more sensitive to PD-1 inhibitors and PD-1 inhibitors combined with CTLA-4 inhibitors. The low rating group may have better efficacy without immune checkpoint inhibitors or with CTLA4 inhibitors alone.Conclusion: Four prognostic hub genes associated with M2 macrophages were screened to establish the M2I Score and divided the patients into two subgroups: high M2I Score group and low M2I Score group. TMB, microsatellite instability and sensitivity to immunotherapy were higher in the high-rated group. PD-1 inhibitors or PD-1 combined with CTLA-4 inhibitors are preferred for patients in the high-rated group who are more sensitive to immunotherapy.

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FOXO1 promotes tumor progression by increased M2 macrophage infiltration in esophageal squamous cell carcinoma

Theranostics ◽

10.7150/thno.45261 ◽

2020 ◽

Vol 10 (25) ◽

pp. 11535-11548

Author(s):

Ying Wang ◽

Zhaojie Lyu ◽

Yanru Qin ◽

Xia Wang ◽

Liangzhan Sun ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Tumor Progression ◽

Cell Carcinoma ◽

Squamous Cell ◽

Macrophage Infiltration ◽

M2 Macrophage

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Galectin-3 Accelerates M2 Macrophage Infiltration and Angiogenesis in Tumors

American Journal Of Pathology ◽

10.1016/j.ajpath.2013.01.017 ◽

2013 ◽

Vol 182 (5) ◽

pp. 1821-1831 ◽

Cited By ~ 40

Author(s):

Weizhen Jia ◽

Hiroyasu Kidoya ◽

Daishi Yamakawa ◽

Hisamichi Naito ◽

Nobuyuki Takakura

Keyword(s):

Macrophage Infiltration ◽

M2 Macrophage ◽

Galectin 3

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Role of CX3CR1 signaling in malignant transformation of gliomas

Neuro-Oncology ◽

10.1093/neuonc/noaa075 ◽

2020 ◽

Vol 22 (10) ◽

pp. 1463-1473 ◽

Cited By ~ 2

Author(s):

Sungho Lee ◽

Khatri Latha ◽

Ganiraju Manyam ◽

Yuhui Yang ◽

Arvind Rao ◽

...

Keyword(s):

Tumor Microenvironment ◽

Mouse Model ◽

Malignant Transformation ◽

Microvessel Density ◽

Progression Free Survival ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

Low Grade ◽

Free Survival

Abstract Background Chemokine signaling may contribute to progression of low-grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3C chemokine receptor 1 (CX3CR1) signaling in malignant transformation of LGGs. Methods Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype-dependent alterations in survival, gene expression, and tumor microenvironment. A genetically engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3C ligand 1 (CX3CL1) and CX3CR1, individually or in combination. Results LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 vs 9.8 y, P < 0.05) and progression-free survival (8.6 vs 6.5 y, P < 0.05) compared with those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, coexpression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival. Conclusions CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.

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Intrahepatic cholangiocarcinoma induced M2-polarized tumor-associated macrophages facilitate tumor growth and invasiveness

Cancer Cell International ◽

10.1186/s12935-020-01687-w ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Hui Yuan ◽

Zelong Lin ◽

Yingjun Liu ◽

Yuchuan Jiang ◽

Ke Liu ◽

...

Keyword(s):

Tumor Growth ◽

Intrahepatic Cholangiocarcinoma ◽

Normal Liver ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

M2 Macrophages ◽

Murine Models ◽

Tumor Associated Macrophages ◽

Stat3 Signaling

Abstract Background M2-polarized tumor-associated macrophages (M2-TAMs) have been shown to correlate with the progression of various cancers, including intrahepatic cholangiocarcinoma (ICC). However, the interactions and mechanism between M2 macrophages and ICC are not completely clear. We aimed to clarify whether M2 macrophages promote the malignancy of ICC and its mechanism. Methods Two progressive murine models of ICC were used to evaluate the alterations in different macrophage populations and phenotypes. Furthermore, we assessed M2 macrophage infiltration in 48 human ICC and 15 normal liver samples. The protumor functions and the underlying molecular mechanisms of M2 macrophages in ICC were investigated in an in vitro coculture system. Results We found that the number of M2 macrophages was significantly higher in ICC tissues than in normal bile ducts in the two murine models. M2 macrophage infiltration was highly increased in peritumoral compared with intratumoral regions and normal liver (p < 0.01). ICC cells induced macrophages to differentiate into the M2-TAM phenotype, and coculture with these M2 macrophages promoted ICC cell proliferation, invasion and epithelial–mesenchymal transition (EMT) in vitro. Mechanistically, M2-TAM-derived IL-10 promoted the malignant properties of ICC cells through STAT3 signaling. Furthermore, blockade of IL-10/STAT3 signaling partly rescued the effects of M2 macrophages on ICC. Conclusion Our results indicated that M2-polarized macrophages induced by ICC promote tumor growth and invasiveness through IL-10/STAT3-induced EMT and might be a potential therapeutic target for ICC.

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