SAMD9 Is Relating With M2 Macrophage and Remarkable Malignancy Characters in Low-Grade Glioma

Immunoreactions regulated by TAMs (Tumor-associated macrophages) play a pivotal role in tumorigenesis and metastasis. In recent decades, treatments based on immune regulation have achieved revolutionary breakthroughs in cancer targeted therapies. The phenotypes of TAMs in gliomas are more heterogeneous and inherently complex than can be simply defined by classification into the M1 and M2 polarized states. The detailed mechanisms surrounding infiltrating macrophage phenotype and glioma characteristics remain undefined. SAMD9 (Sterile Alpha Motif Domain-Containing Protein 9) was found to be highly expressed in glioma and closely related to histological and genetic features in CGGA and TCGA databases. Simultaneously, we present evidence to show that there was a positive association between SAMD9 and malignancy characters in LGG. Univariable and Multivariate proportional hazard Cox analysis showed that SAMD9 was an independent prognostic factor for LGG. Surprisingly, Gene Ontology (GO) analysis showed SAMD9 expression level was remarkably well correlated with immunological responses and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis supported the connection with immune responses and tumorigenesis. Immune infiltration analysis demonstrated that high SAMD9 expression resulted in an accumulation of macrophages by CIBERSORT and TIMER databases, especially positively related to macrophage total marker gene AIF1 and Macrophage M2 marker gene CD163. IHC staining further indicated a high correlation of SAMD9 with those specific macrophage markers in the immune response. Human THP-1 cells were induced into M2 macrophages, which were then co-cultured with LN229 cells. Silencing of SAMD9 by shRNA in LN229 cells attenuated the infiltration abilities of M2 macrophage. SAMD9 explored immune response via relating of M2 macrophage in vitro. Our results revealed SAMD9 acted as the malignancy characters in LGG, enrichment with M2 macrophage.

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Decitabine Promotes Modulation in Phenotype and Function of Monocytes and Macrophages That Drive Immune Response Regulation

Cells ◽

10.3390/cells10040868 ◽

2021 ◽

Vol 10 (4) ◽

pp. 868

Author(s):

Fabiana Albani Zambuzi ◽

Priscilla Mariane Cardoso-Silva ◽

Ricardo Cardoso Castro ◽

Caroline Fontanari ◽

Flavio da Silva Emery ◽

...

Keyword(s):

Immune Response ◽

Hematological Malignancies ◽

M2 Macrophage ◽

M2 Polarization ◽

Tnf Α ◽

Monocytes And Macrophages ◽

Ifn Γ ◽

And Function ◽

The Impact

Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and functions of monocytes and macrophages, which are pivotal cells of the innate immunity system. In vitro decitabine administration increased bacterial phagocytosis and IL-8 release, but impaired microbicidal activity of monocytes. In addition, during monocyte-to-macrophage differentiation, treatment promoted the M2-like profile, with increased expression of CD206 and ALOX15. Macrophages also demonstrated reduced infection control when exposed to Mycobacterium tuberculosis in vitro. However, cytokine production remained unchanged, indicating an atypical M2 macrophage. Furthermore, when macrophages were cocultured with lymphocytes, decitabine induced a reduction in the release of inflammatory cytokines such as IL-1β, TNF-α, and IFN-γ, maintaining IL-10 production, suggesting that decitabine could potentialize M2 polarization and might be considered as a therapeutic against the exacerbated immune response.

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Cationic Nanostructures for the Treatment of Inflammatory Bone Loss

10.21203/rs.3.rs-139744/v1 ◽

2021 ◽

Author(s):

Hanyao Huang ◽

Weiyi Pan ◽

Yi-Fan Wang ◽

Hyesung Kim ◽

Dan Shao ◽

...

Keyword(s):

Bone Loss ◽

Mononuclear Phagocyte ◽

M2 Macrophage ◽

Therapeutic Effects ◽

Macrophage Phenotype ◽

Nucleic Acid Binding ◽

Hydroxyapatite Nanoparticles ◽

Polyamidoamine Dendrimers

Abstract Periodontitis is a common type of inflammatory bone loss and is a risk factor for systemic diseases. The pathogenesis of periodontitis relies on inflammatory dysregulation, which represents a target for new therapeutic strategies to treat periodontitis. Here we demonstrate that cell-free DNA (cfDNA) is correlated with periodontitis in patient samples, and that cfDNA/TLR9 interactions participate in the immune response of periodontitis. We then tested the hypothesis that removing cfDNA would benefit periodontitis treatment. To create nucleic acid-binding nanoparticles (NABNs) specific for periodontitis, we coated bone-mimicking selenium-doped hydroxyapatite nanoparticles with cationic polyamidoamine dendrimers (PAMAM-G3), and compared the activities of these NABNs with those of soluble PAMAM-G3 polymers. Both NABNs and PAMAM-G3 inhibited periodontitis-related inflammation in vitro by scavenging cfDNA, and alleviated inflammatory bone loss in a mouse model of ligature-induced periodontitis. Both cfDNA scavengers also regulated the mononuclear phagocyte system in a periodontitis environment, promoting the M1 over the M2 macrophage phenotype. However, NABNs showed greater therapeutic effects than PAMAM-G3 in terms of scavenging and reducing inflammation and bone loss in vivo. Our findings demonstrate the importance of cfDNA in periodontitis and the potential for using cfDNA-scavenging and hydroxyapatite-based NABNs to ameliorate inflammation and bone loss in periodontitis.

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Contribution of Thrombospondin-1 and -2 to Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

Mediators of Inflammation ◽

10.1155/2021/8876484 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Qiang Li ◽

Xiaoxiao Fu ◽

Jiang Yuan ◽

Shu Han

Keyword(s):

T Regulatory Cells ◽

Inflammatory Diseases ◽

Macrophage Polarization ◽

Endothelial Permeability ◽

M2 Macrophage ◽

Vascular Endothelial ◽

Macrophage Phenotype ◽

Thrombospondin 1

Thrombospondin (TSP) proteins have been shown to impact T-cell adhesion, migration, differentiation, and apoptosis. Thrombospondin-1 (TSP-1) is specifically upregulated in several inflammatory diseases and can effectively promote lipopolysaccharide- (LPS-) induced inflammation. In contrast, thrombospondin-2 (TSP-2) has been associated with activation of “anti-inflammatory” T-regulatory cells (Tregs). In this study, we investigated the effects of both TSP-1 and TSP-2 overexpression on macrophage polarization and activation in vitro and in vivo. We analyzed the effects of TSP-1 and TSP-2 on inflammation, vascular endothelial permeability, edema, ultrastructural morphology, and apoptosis in lung tissues of an ARDS mouse model and cultured macrophages. Our results demonstrated that TSP-2 overexpression effectively attenuated LPS-induced ARDS in vivo and promoted M2 macrophage phenotype polarization in vitro. Furthermore, TSP-2 played a role in regulating pulmonary vascular barrier leakage by activating the PI3K/Akt pathway. Overall, our findings indicate that TSP-2 can modulate inflammation and could therefore be a potential therapeutic target against LPS-induced ARDS.

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Silicone Implants Immobilized with Interleukin-4 Promote the M2 Polarization of Macrophages and Inhibit the Formation of Fibrous Capsules

Polymers ◽

10.3390/polym13162630 ◽

2021 ◽

Vol 13 (16) ◽

pp. 2630

Author(s):

Hyun-Seok Kim ◽

Seongsoo Kim ◽

Byung-Ho Shin ◽

Chan-Yeong Heo ◽

Omar Faruq ◽

...

Keyword(s):

Tissue Regeneration ◽

Capsular Contracture ◽

Silicone Implant ◽

Interleukin 4 ◽

Silicone Implants ◽

M2 Macrophage ◽

Macrophage Phenotype ◽

Arginase 1

Breast augmentations with silicone implants can have adverse effects on tissues that, in turn, lead to capsular contracture (CC). One of the potential ways of overcoming CC is to control the implant/host interaction using immunomodulatory agents. Recently, a high ratio of anti-inflammatory (M2) macrophages to pro-inflammatory (M1) macrophages has been reported to be an effective tissue regeneration approach at the implant site. In this study, a biofunctionalized implant was coated with interleukin (IL)-4 to inhibit an adverse immune reaction and promoted tissue regeneration by promoting polarization of macrophages into the M2 pro-healing phenotype in the long term. Surface wettability, nitrogen content, and atomic force microscopy data clearly showed the successful immobilization of IL-4 on the silicone implant. Furthermore, in vitro results revealed that IL-4-coated implants were able to decrease the secretion of inflammatory cytokines (IL-6 and tumor necrosis factor-α) and induced the production of IL-10 and the upregulation of arginase-1 (mannose receptor expressed by M2 macrophage). The efficacy of this immunomodulatory implant was further demonstrated in an in vivo rat model. The animal study showed that the presence of IL-4 diminished the capsule thickness, the amount of collagen, tissue inflammation, and the infiltration of fibroblasts and myofibroblasts. These results suggest that macrophage phenotype modulation can effectively reduce inflammation and fibrous CC on a silicone implant conjugated with IL-4.

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The mmu_circ_0000335 inhibits M1 microglial-induced hippocampal neuronal apoptosis via the miR-19b-3p/SOCS1 axis in a mouse epilepsy model

10.21203/rs.2.16568/v1 ◽

2019 ◽

Author(s):

Yong Zhu ◽

Qiong Li ◽

Weiping Kuang ◽

Jun Lu ◽

Qin Wang ◽

...

Keyword(s):

In Vivo Studies ◽

Luciferase Reporter ◽

Circular Rnas ◽

Cytokine Signaling ◽

M2 Macrophage ◽

Macrophage Phenotype ◽

Bioinformatics Analyses ◽

M1 Macrophage

Abstract Background : Increasing evidence has demonstrated that circular RNAs (circRNAs) participate in epileptogenesis, but the expression profile and role of circRNAs in epilepsy remain unknown. A circRNA microarray was performed to examine epilepsy-related circRNAs. Bioinformatics analyses, luciferin reporter experiments and real-time quantitative PCR (Rt-qPCR) in vitro experiments were performed to demonstrate the mechanism of circRNA-mediated gene regulation of the microglial phenotype under epileptic conditions. Then, to further confirm the effect of circRNAs on nerve damage in the hippocampus, a mouse model of epilepsy was established by intraperitoneal injection of lithium chloride and pilocarpine. Results: The data indicated that 364 circRNAs were differentially expressed comparing epilepsy and control tissues. In particular, mmu_circ_0000335 expression was significantly downregulated in epileptic mice which was confirmed by Rt-qPCR. Overexpression of mmu_circ_0000335 promoted BV2 cell transformation into the M2 macrophage phenotype by increasing expression of CD206, Arg1, Ym1 and IL-10 while decreasing M1 macrophage markers IL-1β, IL-6, TNF-α and IFN-γ expressions under epileptic conditions. mmu_circ_0000335 expression triggered upregulation of Suppressor of Cytokine Signaling 1 (SOCS1) by decreasing miR-19b-3p levels, as determined by luciferase reporter assay. In vivo studies found that mmu_circ_0000335 overexpression decreased epilepsy-induced neural cell apoptosis in the hippocampus by reducing inflammatory cytokine expression. Immunofluorescence detection showed that mmu_circ_0000335 overexpression promoted microglial transformation into the M2 phenotype which had an anti-inflammatory effect. Conclusions: These results collectively indicated that mmu_circ_0000335 was involved in epilepsy progression by functioning as a miR-19b-3p sponge to enhance SOCS1 expression. Thus, mmu_circ_0000335 may be a candidate therapeutic target for epilepsy patients.

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SAT0300 SERUM FROM “EARLY” SYSTEMIC SCLEROSIS PATIENTS ALREADY INDUCES THE ALTERNATIVELY ACTIVATED MACROPHAGE PHENOTYPE (M2) IN CULTURED HUMAN MONOCYTES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4552 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1095-1095

Author(s):

S. Soldano ◽

S. Tardito ◽

S. Paolino ◽

M. Patanè ◽

E. Gotelli ◽

...

Keyword(s):

Systemic Sclerosis ◽

Healthy Subjects ◽

M2 Macrophage ◽

M2 Macrophages ◽

Macrophage Phenotype ◽

Skin Involvement ◽

Research Support ◽

Circulating Cells ◽

Alternatively Activated

Background:Alternatively activated (M2) macrophages seem to play a role in the fibrotic process of systemic sclerosis (SSc) as potential inducers of tissue fibrosis through their secretion of specific cytokines and chemokines, such as interleukin-10 (IL-10), macrophage derived chemokine (CCL-22) and pro-fibrotic metalloproteases (i.e. MMP9) (1-3).Objectives:To investigate the presence of circulating cells belonging to the monocyte lineage showing an M2 phenotype in SSc patients (pts) and possible correlation with the clinical parameters of the disease. Moreover, to investigate if the treatment of cultured monocytes isolated from healthy subjects with serum derived from early SSc pts may induce theirin vitropolarization into M2 macrophages.Methods:Fifty female SSc pts (mean age 64±13 yrs), fulfilling the EULAR/ACR criteria, and 27 gender-matched healthy subjects (HSs, mean age 57±7 yrs) were considered at the Rheumatology Division of Genoa University after written informed consent. Nailfold videocapillaroscopy (NVC), serum SSc-related antibodies and skin involvement were investigated. Circulating cells belonging to the monocyte populations (CD45+and CD14+cells) were characterised by flow cytometry using specific surface markers of M2 phenotypes (CD204, CD206, CD163). Each SSc pt had been under stable treatment regimen for at least six months. Cultured monocytes, isolated by negative selection from peripheral blood mononuclear cells (PBMCs) of 8 HSs, stimulated for 48 hrs with 10% of serum of lcSSc pts with “Early” NVC pattern, as well as serum of dcSSc pts with “Active” and “Late” NVC patterns. Cultured monocyte human cell line (THP1) was differentiated into macrophages (5ng/ml of phorbol myristate acetate) and then stimulated with SSc sera. The expression of CD204, CD206 (M2 markers) and CD68 was investigated by immunocytochemistry, whereas MMP9 secretion was investigated by zymography. Statistical analysis was performed using Mann-Whitney and Kruskal-Wallis tests, and correlations were explored by bivariate Pearson’s analysis.Results:In SSc pts the percentage of circulating M2 cells (CD14+CD204+CD163+CD206+cells) was significantly increased compared to both HSs and SSc pts not under immunosuppressive treatment (p<0.05) However, no correlation with skin involvement and SSc-related antibodies was observed. Cultured macrophages stimulated with SSc serum expressed CD204 and CD206 markers compared to the macrophages stimulated with HS serum (CD204 and CD206 double negative cells). Of note, the ability to express M2 markers was already evident in cultured macrophages stimulated with “Early” NVC SSc serum and their expression even increased in macrophages stimulated with “Active” and “Late” NVC sera together with the secretion of MMP9. Same results were observed also in cultured THP1-derived macrophages.Conclusion:The study confirmed that SSc pts are characterized by a significant increase of circulating M2 cells, suggesting their possible involvement in the pathogenesis of the disease. Interestingly, results insinuate that sera from SSc patients already in an “Early” NVC condition (sera known to contains specific profibrotic molecules such as cytokines, growth factors like TGFb1 or endothelin-1) seem able to inducein vitroa profibrotic M2 macrophage phenotype.References:[1]Cutolo M et al. ExpRevClin Immunol. 2019;15:753-64.[2]Stifano G et al. Curr Rheumatol Rep. 2016; 18:2. doi: 10.1007/s11926-015-0554-8.[3]Medeiros NI et al. Parasite Immunol. 2017;39: doi: 10.1111/pim.12446.Disclosure of Interests:Stefano Soldano: None declared, Samuele Tardito: None declared, Sabrina Paolino: None declared, Massimo Patanè: None declared, Emanuele Gotelli: None declared, Claudio Corallo: None declared, Carmen Pizzorni: None declared, Greta Pacini: None declared, Federica Goegan: None declared, Alberto Sulli Grant/research support from: Laboratori Baldacci, Carlotta Schenone: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha

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Lipids derived from Camel milk regulate NLRP3 inflammasome-dependent inflammatory responses in human macrophages

Functional Foods in Health and Disease ◽

10.31989/ffhd.v9i4.567 ◽

2019 ◽

Vol 9 (4) ◽

pp. 224 ◽

Cited By ~ 1

Author(s):

Raya Hamdan Al-Nasseri ◽

Huda Al-Ruqashi ◽

Jamal Al-Sabahi ◽

Ahmed Al-Harrasi ◽

Ara Kenekanian ◽

...

Keyword(s):

Fatty Acids ◽

Nlrp3 Inflammasome ◽

Unsaturated Fatty Acids ◽

Inflammatory Responses ◽

Camel Milk ◽

Gas Chromatography Mass Spectrometry ◽

M2 Macrophage ◽

Macrophage Phenotype ◽

Milk Lipids

Background: Camel milk is widely used for its reported anti-diabetic and health promoting effects. Lipids derived from the milk have also been shown to exhibit potent anti-inflammatory effects. The mechanism through which these lipids and constituent fatty acids exert these effects remains elusive. The aim of this study was to investigate the effect of camel milk on glycated protein-mediated macrophage inflammation.Methods: To determine the effect of Total Lipids (TL) and Total Fatty Acids (TFA) derived from camel milk on an in vitro model of diabetic inflammation, differentiated THP-1 (dTHP-1) cells stimulated with glycated serum albumin (gBSA) was employed. Cells were pre-treated with TL or TFA before challenging cells with gBSA.Results: Gas Chromatography-Mass Spectrometry (GC-MS) analysis found that TL was 96% triacylglycerol (TAG) while the TFA comprised 65% saturated and 35% unsaturated fatty acids. Both TL and TFA significantly (p<0.05) decreased gBSA-induced secretion of pro-inflammatory cytokines (Tumour necrosis factor-(TNF)-α, Interleukin-(IL)-1β/18). TL also demonstrated the ability to regulate the expression of p50/p65 sub-units of Nuclear Factor-kappa B (NF-κB), while concomitantly increasing the expression of regulatory cytokines IL-10, IL-1 Receptor Antagonist (IL-1Ra) and Cluster of Differentiation 163 (CD163)-shifting cells towards an M2 macrophage phenotype. Additionally, we found that TL significantly regulated the expression of Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing-3 (NLRP3) inflammasome subunit and its regulator; Ten-Eleven Translocation-2 (TET-2).Conclusion: This paper demonstrates the ability of camel milk lipids to regulate gBSA-induced macrophage inflammation in vitro, by modulating the expression of key inflammatory regulators such NF-kB and NLRP3 inflammasome subunit. Keywords: Camel milk lipids, Macrophages, NF-kB, NLRP3-inflammasome, TET-2

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Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Frontiers in Medicine ◽

10.3389/fmed.2021.627927 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sujuan Xi ◽

Xiaoyan Zheng ◽

Xiangyong Li ◽

Yuming Jiang ◽

Yuankai Wu ◽

...

Keyword(s):

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

M2 Macrophage ◽

Macrophage Phenotype ◽

Macrophage Marker ◽

Activated Hepatic Stellate Cells ◽

And Function ◽

M2 Phenotype

Background: Activated hepatic stellate cells (aHSCs) regulate the function of immune cells during liver fibrosis. As major innate cells in the liver, macrophages have inducible plasticity. Nevertheless, the mechanisms through which aHSCs regulate macrophages' phenotype and function during liver fibrosis and cirrhosis remain unclear. In this study, we examined the immunoregulatory function of aHSCs during liver fibrosis and explored their role in regulating macrophage phenotype and function.Methods: A total of 96 patients with different stages of chronic hepatitis B-related liver fibrosis were recruited in the study. Metavir score system was used to evaluate the degree of fibrosis. The expression of hepatic CCL2 and M2 phenotype macrophage marker CD163 were detected by immunohistochemistry, and the relationship among hepatic CD163, CCL2, and fibrosis scores were also explored. In the in vitro model, the aHSCs isolated from human liver tissues and THP-1-derived M0-type macrophages (M0MΦ) were co-cultured to observe whether and how aHSCs regulate the phenotype and function of macrophages. To explore whether CCL2/CCR2 axis has a crucial role in macrophage phenotypic changes during liver fibrosis, we treated the M0MΦ with recombinant human CCL2 or its specific receptor antagonist INCB-3284. Furthermore, we used LX2 and TGF-β-activated LX2 to mimic the different activation statuses of aHSCs to further confirm our results.Results: In patients, the infiltration of M2 macrophages increased during the progression of liver fibrosis. Intriguingly, as a key molecule for aHSC chemotactic macrophage aggregation, CCL2 markedly up-regulated the expression of CD163 and CD206 on the macrophages, which was further confirmed by adding the CCR2 antagonist (INCB 3284) into the cell culture system. In addition, the TGF-β stimulated LX2 further confirmed that aHSCs up-regulate the expression of CD163 and CD206 on macrophages. LX2 stimulated with TGF-β could produce more CCL2 and up-regulate other M2 phenotype macrophage-specific markers, including IL-10, ARG-1, and CCR2 besides CD163 and CD206 at the gene level, indicating that the different activation status of aHSCs might affect the final phenotype and function of macrophages.Conclusions: The expression of the M2 macrophage marker increases during liver fibrosis progression and is associated with fibrosis severity. AHSCs can recruit macrophages through the CCL2/CCR2 pathway and induce M2 phenotypic transformation.

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