ETS1-mediated Regulation of SOAT1 Enhances the Malignant Phenotype of Oral Squamous Cell Carcinoma and Induces Tumor-associated Macrophages M2-like Polarization
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ABSTRACT:
SUBMITTER: Liu Y
PROVIDER: S-EPMC11234219 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundImmunotherapy has brought new hope to gastric cancer (GC) patients. Exploring the immune infiltration pattern in GC and the key molecules is critical for optimizing the efficacy of immunotherapy. Aldo-keto reductase family 1 member B10 (AKR1B10) is an inflammatory regulator and is closely related to the prognosis of patients with GC. However, the function of AKR1B10 in GC remains unclear.MethodsIn the present study, the CIBERSORT algorithm was used to analyze the immune infiltration pattern in 373 samples in the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were seared by combing the TCGA database and the Gene Expression Omnibus (GEO) database, and the key molecule AKR1B10 was identified by weighted gene coexpression network analysis (WGCNA). The biological functions of AKR1B10 in stomach adenocarcinoma (STAD) were investigated in vitro.ResultsMacrophage polarization was the main immune infiltration pattern in GC, and the state of macrophage polarization was closely related to the pathological grading of GC and the clinical stage of patients. AKR1B10, MUC5AC, TFF2, GKN1, and PGC were significantly down-regulated in GC tissues. Low AKR1B10 expression induced M2 macrophage polarization and promoted the malignant phenotype of GC.ConclusionM2 macrophage polarization is the main immune infiltration pattern in GC. Low AKR1B10 expression induces M2 macrophage polarization and promotes the malignant transformation of GC.
| S-EPMC10545534 | biostudies-literature
Project description:Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation.
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Project description:Alpha-fetoprotein(AFP) is a cancer biomarker for the diagnosis of hepatocellular carcinoma(HCC); however, its role in macrophage polarization and phagocytosis remains unclear. In the present study, we explored the correlation between AFP regulation of macrophage function and the possible regulatory mechanisms. Human mononuclear leukemia cells (THP-1) and monocytes from healthy donors were used to analyze the effect of AFP on the macrophages' phenotype and phagocytosis. THP-1 cells and healthy human donor-derived monocytes were polarized into M0 macrophages induced by phorbol ester (PMA), and M0 macrophages were polarized into M1 macrophages induced by lipopolysaccharide(LPS) and interferon-γ(IFN-γ). Interleukin-4(IL-4) and interleukin-13(IL-13) were used to induce M0 macrophage polarization into M2 macrophages. Tumor-derived AFP(tAFP) stimulated M0 macrophage polarization into M2 macrophages and inhibited M1 macrophages to phagocytize HCC cells. The role of AFP in promoting macrophage polarization into M2 macrophages and inhibiting the M1 macrophages to phagocytize HCC cells may be involved in activating the PI3K/Akt signaling pathway. AFP could also enhanced the migration ability of macrophages and inhibited the apoptosis of HCC cells when co-cultured with M1-like macrophages. AFP is a pivotal cytokine that inhibits macrophages to phagocytize HCC cells.
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Project description:Reticulocalbin 1 (RCN1), a calcium-binding protein located in the endoplasmic reticulum (ER) lumen, contains six conserved regions. Its main functions include maintaining intracellular homeostasis and regulating cell proliferation and apoptosis, and it plays an important role in the development of various tumours. However, the exact function of RCN1 in oral squamous cell carcinoma (OSCC) is not fully understood. Therefore, the aim of this study was to investigate the effects of RCN1 on the biological behaviour of OSCC and the regulation of tumour-associated macrophage (TAM) polarization. The expression of RCN1 in OSCC and normal oral mucosa was evaluated through bioinformatics analysis and immunohistochemical staining. The growth, migration, and invasion of OSCC cells were observed after knockdown of RCN1 using CCK-8 and Transwell assays. Apoptosis was detected by flow cytometry. The effect of tumour cell-derived RCN1 on the polarization of THP-1 macrophages was investigated by establishing a coculture model of THP-1 macrophages and OSCC cells. Additionally, changes in the expression levels of relevant proteins were detected using Western blotting. The upregulation of RCN1 in tumour tissues compared to normal oral mucosal tissues is associated with a poor prognosis and can be utilized as a prognostic indicator for OSCC. Knockdown of RCN1 inhibited the proliferation, migration, and invasion of OSCC cells. Additionally, knockdown of RCN1 in Cal-27 and SCC-25 cells resulted in inhibition of the M2 polarization of THP-1 macrophages. RCN1 knockdown inhibits OSCC progression and M2 macrophage polarization. Targeting RCN1 may be a promising approach for OSCC treatment.
| S-EPMC10700561 | biostudies-literature
Project description:Atherosclerosis (AS) is characterized as progressive arterial plaque, which is easy to rupture under low stability. Macrophage polarization and inflammation response plays an important role in regulating plaque stability. Ginsenoside Rb1 (Rb1), one of the main active principles of Panax Ginseng, has been found powerful potential in alleviating inflammatory response. However, whether Rb1 could exert protective effects on AS plaque stability remains unclear. This study investigated the role of Rb1 on macrophage polarization and atherosclerotic plaque stability using primary peritoneal macrophages isolated from C57BL/6 mice and AS model in ApoE-/- mice. In vitro, Rb1 treatment promoted the expression of arginase-I (Arg-I) and macrophage mannose receptor (CD206), two classic M2 macrophages markers, while the expression of iNOS (M1 macrophages) was decreased. Rb1 increased interleukin-4 (IL-4) and interleukin-13 (IL-13) secretion in supernatant and promoted STAT6 phosphorylation. IL-4 and/or IL-13 neutralizing antibodies and leflunomide, a STAT6 inhibitor attenuated the up-regulation of M2 markers induced by Rb1. In vivo, the administration of Rb1 promoted atherosclerotic lesion stability, accompanied by increased M2 macrophage phenotype and reduced MMP-9 staining. These data suggested that Rb1 enhanced atherosclerotic plaque stability through promoting anti-inflammatory M2 macrophage polarization, which is achieved partly by increasing the production of IL-4 and/or IL-13 and STAT6 phosphorylation. Our study provides new evidence for possibility of Rb1 in prevention and treatment of atherosclerosis.
| S-EPMC5742675 | biostudies-literature
Project description:Pirfenidone is a representative medication to treat interstitial pulmonary fibrosis. Researchers reported pirfenidone (>100 µg/ml) significantly suppressed fibroblast growth in vitro. However, clinically, the maximum concentration of pirfenidone in the blood is approximately 10 µg/ml. We hypothesized there might be an additional mechanism of pirfenidone to fibroblasts indirectly. Macrophages are known to control the activation of fibroblasts via the regulation of inflammatory M1 and suppressive M2 polarization. The aim of this study was to investigate the effects of pirfenidone on alveolar macrophage polarization. Rat alveolar macrophages (NR8383) were stimulated in vitro with lipopolysaccharide (LPS) + interferon (IFN)-γ, or interleukin (IL)-4 + IL-13. Expression of M1 and M2 markers and supernatant's levels of TGF-β1 were assessed after pirfenidone treatment (0-100 µg/ml). Treatment with LPS + INF-γ or IL-4 + IL-13 significantly increased the expression of M1 and M2 markers, respectively. In macrophage polarization assays, pirfenidone significantly reduced the expression of M2 markers at concentrations greater than 10 µg/ml but had no effect on the expression of M1 markers. At these concentrations, pirfenidone significantly reduced TGF-β1 levels in NR8383 culture supernatants. In rat lung fibroblasts treated with NR8383 culture supernatants, pirfenidone significantly suppressed proliferation, and the collagen mRNA and protein levels. In conclusion, our results demonstrated that pirfenidone suppressed polarization to M2 macrophages at clinically relevant concentrations and suppressed the rat lung fibroblasts fibrogenic activity.
| S-EPMC6064814 | biostudies-literature
Project description:Pleural macrophages play critical roles in pathogenesis of tuberculous pleuritis, but very little is known about their response to anti-tuberculosis antibiotics treatment. Here, we examined whether and how pleural macrophages change in phenotype, transcription and function following antibiotics treatment in patients with tuberculous pleuritis. Results show pro-inflammatory cytokines were down-regulated significantly post antibiotic treatment in the pleural effusions and pleural macrophages up-regulated markers characteristic of M2 macrophages such as CD163 and CD206. Differential expression analysis of transcriptomes from four paired samples before and after treatment identified 230 treatment-specific responsive genes in pleural macrophages. Functional analysis identified interferon-related pathway to be the most responsive genes and further confirmed macrophage polarization to M2-like phenotype. We further demonstrate that expression of a significant fraction of responsive genes was modulated directly by antibiotics in pleural macrophages in vitro. Our results conclude that pleural macrophages polarize from M1-like to M2-like phenotype within a mean of 3.5 days post antibiotics treatment, which is dependent on both pleural cytokine environment and direct modulatory effects of antibiotics. The treatment-specific genes could be used to study the roles of pleural macrophages in the pathogenesis of tuberculous pleuritis and to monitor the response to antibiotics treatment.
| S-EPMC5670217 | biostudies-literature
Project description:Multiple sclerosis (MS) is a chronic and debilitating neurological disorder of the central nervous system (CNS), characterized by infiltration of leukocytes into CNS and subsequent demyelination. Emerging evidences have revealed the beneficial roles of M2 macrophages in ameliorating experimental autoimmune encephalomyelitis (EAE), a model for MS. Here, we identify that lenalidomide alone could promote macrophages M2 polarization to prevent the progression of EAE, which is associated with subsequent inhibition of proinflammatory Th1 and Th17 cells both in peripheral lymph system and CNS. Depletion of macrophages by pharmacology treatment of clodronate liposomes or transferring lenalidomide-induced BMDMs in EAE mice completely abolished the therapeutic effect of lenalidomide or prevented EAE development, respectively. The macrophages-derived IL10 was upregulated both in vivo and in vitro after lenalidomide treatment. Moreover, lenalidomide-treated IL10-dificient EAE mice had higher clinical scores and more severe CNS damage, and intravenous injection of lenalidomide-treated IL10-/- BMDMs into mice with EAE at disease onset did not reverse disease severity, implying IL10 may be essential in lenalidomide-ameliorated EAE. Mechanistically, lenalidomide significantly increased expression and autocrine secretion of IL10, subsequently activated STAT3-mediated expression of Ym1. These studies facilitate the development of potential novel therapeutic application of lenalidomide for the treatment of MS.
| S-EPMC5833426 | biostudies-literature
Project description:BackgroundMacrophages are effector cells of the innate immune system that undergo phenotypical changes in response to organ injury and repair. These cells are most often classified as proinflammatory M1 and anti-inflammatory M2 macrophages. Protein arginine deiminase (PAD), which catalyses the irreversible conversion of protein-bound arginine into citrulline, is expressed in macrophages. However, the substrates of PAD and its role in immune cells remain unclear. This study aimed to investigate the role of PAD in THP-1 macrophage polarization to the M1 and M2 phenotypes and identify the citrullinated proteins and modified arginines that are associated with this biological switch using mass spectrometry.ResultsOur study showed that PAD2 and, to a lesser extent, PAD1 and PAD4 were predominantly expressed in M1 macrophages. We showed that inhibiting PAD expression with BB-Cl-amidine decreased macrophage polarization to the M1 phenotype (TNF-α, IL-6) and increased macrophage polarization to the M2 phenotype (MRC1, ALOX15). This process was mediated by the downregulation of proteins involved in the NF-κβ pathway. Silencing PAD2 confirmed the activation of M2 macrophages by increasing the antiviral innate immune response and interferon signalling. A total of 192 novel citrullination sites associated with inflammation, cell death and DNA/RNA processing pathways were identified in M1 and M2 macrophages.ConclusionsWe showed that inhibiting PAD activity using a pharmacological inhibitor or silencing PAD2 with PAD2 siRNA shifted the activation of macrophages towards the M2 phenotype, which can be crucial for designing novel macrophage-mediated therapeutic strategies. We revealed a major citrullinated proteome and its rearrangement following macrophage polarization, which after further validation could lead to significant clinical benefits for the treatment of inflammation and autoimmune diseases.
| S-EPMC9675280 | biostudies-literature
Project description:Tissue repair is largely regulated by diverse Mϕ populations whose functions are timing- and context-dependent. The early phase of healing is dominated by pro-inflammatory Mϕs, also known as M1, followed by the emergence of a distinct and diverse population that is collectively referred to as M2. The extent of the diversity of the M2 population is unknown. M2 Mϕs may originate directly from circulating monocytes or from phenotypic switching of pre-existing M1 Mϕs within the site of injury. The differences between these groups are poorly understood, but have major implications for understanding and treating pathologies characterized by deficient M2 activation, such as chronic wounds, which also exhibit diminished M1 Mϕ behavior. This study investigated the influence of prior M1 activation on human Mϕ polarization to an M2 phenotype in response to IL-4 treatment in vitro. Compared to unactivated (M0) Mϕs, M1 Mϕs up-regulated several receptors that promote the M2 phenotype, including the primary receptor for IL-4. M1 Mϕs also up-regulated M2 markers in response to lower doses of IL-4, including doses as low as 10 pg/mL, and accelerated STAT6 phosphorylation. However, M1 activation appeared to also change the Mϕ response to treatment with IL-4, generating an M2-like phenotype with a distinct gene and protein expression signature compared to M2 Mϕs prepared directly from M0 Mϕs. Functionally, compared to M0-derived M2 Mϕs, M1-derived M2 Mϕs demonstrated increased migratory response to SDF-1α, and conditioned media from these Mϕs promoted increased migration of endothelial cells in transwell assays, although other common Mϕ-associated functions such as phagocytosis were not affected by prior polarization state. In summary, M1 polarization appears to prime Mϕs to transition into a distinct M2 phenotype in response to IL4, which leads to increased expression of some genes and proteins and decreased expression of others, as well as functional differences. Together, these findings indicate the importance of prior M1 activation in regulating subsequent M2 behavior, and suggest that correcting M1 behavior may be a therapeutic target in dysfunctional M2 activation.
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