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Clear cell renal cell carcinoma (ccRCC) represents a highly heterogeneous kidney malignancy associated with the poorest prognosis. The metastatic potential of advanced ccRCC tumors is notably high, posing significant clinical challenges. There is an urgent imperative to develop novel therapeutic approaches to address ccRCC metastasis. Recent investigations indicated a potential association between GBP2 and tumor immunity. However, the precise functional role of GBP2 in the progression of ccRCC remains poorly understood. The present study revealed a strong correlation between GBP2 and M2 macrophages. Specifically, our findings demonstrated that the inhibition of GBP2 significantly impedes the migratory and invasive capabilities of ccRCC cells. We observed that the presence of M2 macrophages can reverse the effects of GBP2 knockdown on tumor cell migration and invasion. Mechanistically, we demonstrated that M2 macrophages promote the expression of the GBP2/p‐STAT3 and p‐ERK axis in tumor cells through the secretion of interleukin‐10 (IL‐10) and transforming growth factor‐β (TGF‐β), thereby substantially enhancing the migratory and invasive capacities of the tumor cells. Simultaneously, we have identified that GBP2 promotes the polarization of macrophages to the M2 phenotype by stimulating the secretion of interleukin‐18 (IL‐18). In summary, our investigation anticipates that the GBP2/IL‐18/M2 macrophages/IL‐10 and the TGF‐β/GBP2, p‐STAT3, p‐ERK loop plays a crucial role in ccRCC metastasis. The collective findings from our research underscore the significant role of GBP2 in tumor immunity and emphasize the potential for modulating GBP2 as a promising therapeutic strategy for targeting ccRCC metastasis. [ABSTRACT FROM AUTHOR]

Background: Although the representative treatment for colorectal cancer (CRC) is radiotherapy, cancer cells survive due to inherent radioresistance or resistance acquired after radiation treatment, accelerating tumor malignancy and causing local recurrence and metastasis. However, the detailed mechanisms of malignancy induced after radiotherapy are not well understood. To develop more effective and improved radiotherapy and diagnostic methods, it is necessary to clearly identify the mechanisms of radioresistance and discover related biomarkers. Methods: To analyze the expression pattern of miRNAs in radioresistant CRC, sequence analysis was performed in radioresistant HCT116 cells using Gene Expression Omnibus, and then miR-1226-5p, which had the highest expression in resistant cells compared to parental cells, was selected. To confirm the effect of miR-1226-5 on tumorigenicity, Western blot, qRT-PCR, transwell migration, and invasion assays were performed to confirm the expression of EMT factors, cell mobility and invasiveness. Additionally, the tumorigenic ability of miR-1226-5p was confirmed in organoids derived from colorectal cancer patients. In CRC cells, IRF1, a target gene of miR-1226-5p, and circSLC43A1, which acts as a sponge for miR-1226-5p, were discovered and the mechanism was analyzed by confirming the tumorigenic phenotype. To analyze the effect of tumor-derived miR-1226-5p on macrophages, the expression of M2 marker in co-cultured cells and CRC patient tissues were confirmed by qRT-PCR and immunohistochemical (IHC) staining analyses. Results: This study found that overexpressed miR-1226-5p in radioresistant CRC dramatically promoted epithelial-mesenchymal transition (EMT), migration, invasion, and tumor growth by suppressing the expression of its target gene, IRF1. Additionally, we discovered circSLC43A1, a factor that acts as a sponge for miR-1226-5p and suppresses its expression, and verified that EMT, migration, invasion, and tumor growth are suppressed by circSLC43A1 in radioresistant CRC cells. Resistant CRC cells-derived miR-1226-5p was transferred to macrophages and contributed to tumorigenicity by inducing M2 polarization and secretion of TGF-β. Conclusions: This study showed that the circSLC43A1/miR-1226-5p/IRF1 axis is involved in radioresistance and cancer aggressiveness in CRC. It was suggested that the discovered signaling factors could be used as potential biomarkers for diagnosis and treatment of radioresistant CRC. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous tumor. Commonly used tumor staging don't sufficiently and accurately assess the prognosis of HNSCC patients, resulting in a lack of guidance for clinical treatment decisions. M2 macrophage infiltration has been shown to be strongly associated with the tumor prognosis. In this study, we used the Cancer Genome Atlas (TCGA) data to screen for genes co-expressed with M2 macrophages in HNSCC. We used univariate Cox regression to screen out the genes associated with HNSCC prognosis, and constructed a HNSCC prognosis model by Lasso regression analysis. The results confirmed that the model had good predictive value and accuracy for the prognosis of HNSCC patients by survival analysis, ROC curve and nomogram. We divided the HNSCC samples into high-risk and low-risk groups according to the risk score, and the results showed that patients in the high-risk group were more prone to genetic mutations and had a higher tumor mutational burden. In addition, there were significant differences between risk groups in terms of immune cell infiltration and drug sensitivity. The HNSCC prognostic model established in this study may provide guidance for clinical therapeutic decision-making and provide a theoretical foundation for the development of new immunotherapy methods. [ABSTRACT FROM AUTHOR]

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Background: The BEAN1 gene, primarily studied in neurodegenerative diseases, has been scarcely studied in the context of cancers. Our research examines BEAN1 expression specifically in rectal adenocarcinoma (READ) and its association with prognosis, immune evasion, and chemotherapy resistance. Methods: Data from TCGA and GEO were analyzed to assess BEAN1 levels across various cancer types, with particular emphasis on READ. Functional enrichment, immune infiltration, and treatment response analyses were conducted, followed by validation using patient tissue samples. Results: READ tissues exhibited a marked increase in BEAN1 expression compared to normal tissues. Elevated BEAN1 levels were associated with reduced overall survival and increased immune suppression, characterized by elevated M2 macrophage infiltration and reduced CD8+ T cell presence. BEAN1 expression was also linked to higher immune checkpoint genes expression and resistance to immune checkpoint inhibitors and 5-fluorouracil. Conclusion: This research offers initial evidence that BEAN1 is linked to unfavorable prognosis, immune escape, and resistance to chemotherapy in READ. BEAN1 appears to be a promising new biomarker and potential therapeutic target, warranting further investigation into its potential clinical applications in improving treatment outcomes for READ patients. [ABSTRACT FROM AUTHOR]

Organ structure destruction and functional decline leading to failure due to fibrosis pose severe threats to the human health and life. Macrophages are important immune cells present in various tissues and organs. Under the influence of numerous factors and pathways, such as transforming growth factor-β1 (TGF-β1), Toll-like receptor 4 (TLR4) /nuclear factor-κB (NF-κB), Janus kinase (JAK) /signal transducer and activator of transcription (STAT), Notch signaling pathway, peroxisome proliferator-activated receptor (PPAR), and cAMP response element-binding protein (CREB), the macrophages may undergo polarization. In visceral organ fibrosis, the macrophage polarization signaling network, composed of single or multiple factors and pathways, is one of the crucial mechanisms regulating fibrosis. After polarization, the macrophages produce the chemokines and matrix metalloproteinase (MMP), which are related to promoting fibrosis, leading to the occurrence and development of fibrosis. The current research conducted domestically and internationally mainly focuses on the roles of macrophages in infection, tumors, and fibrosis, with few summaries on the mechanisms of macrophage polarization in fibrosis. This review summarizes the pathways involved in macrophage polarization and the mechanisms of macrophage polarization in organ fibrosis, and provide the basis for the targeted therapy of fibrosis. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are inflammatory cells that are important components of the tumor microenvironment. TAMs are functionally heterogeneous and divided into two main subpopulations with distinct and opposite functions: M1 and M2 macrophages. The secretory function of TAMs is essential for combating infections, regulating immune responses, and promoting tissue repair. Extracellular vesicles (EVs) are nanovesicles that are secreted by cells. They play a crucial role in mediating intercellular information transfer between cells. EVs can be secreted by almost all types of cells, and they contain proteins, microRNAs, mRNAs, and even long non-coding RNAs (lncRNAs) that have been retained from the parental cell through the process of biogenesis. EVs can influence the function and behavior of target cells by delivering their contents, thus reflecting, to some extent, the characteristics of their parental cells. Here, we provide an overview of the role of M1 macrophages and their EVs in cancer therapy by exploring the impact of M1 macrophage-derived EVs (M1-EVs) on tumors by transferring small microRNAs. Additionally, we discuss the potential of M1-EVs as drug carriers and the possibility of reprogramming M2 macrophages into M1 macrophages for disease treatment. We propose that M1-EVs play a crucial role in cancer therapy by transferring microRNAs and loading them with drugs. Reprogramming M2 macrophages into M1 macrophages holds great promise in the treatment of cancers. [ABSTRACT FROM AUTHOR]

Neurotrophin-3 (NT-3) is an important family of neurotrophic factors with extensive neurotrophic activity, which can maintain the survival and regeneration of nerve cells. However, the mechanism of NT-3 on macrophage phenotype transformation after sciatic nerve injury is not clear. In this study, we constructed a scientific nerve compression injury animal model and administered different doses of NT-3 treatment through osmotic minipump. 7 days after surgery, we collected sciatic nerve tissue and observed the distribution of macrophage phenotype through iNOS and CD206 immunofluorescence. During the experiment, regular postoperative observations were conducted on rats. After the experiment, sciatic nerve tissue was collected for HE staining, myelin staining, immunofluorescence staining, and Western blot analysis. To verify the role of the AMPK/NF-κB pathway, we applied the AMPK inhibitor Compound C and the NF-κB inhibitor BAY11-7082 to repeat the above experiment. Our experimental results reveal that NT-3 promotes sciatic nerve injury repair and polarization of M2 macrophage phenotype, promotes AMPK activation, and inhibits NF-κB activation. The repair effect of high concentration NT-3 on sciatic nerve injury is significantly enhanced compared to low concentration. Compound C administration can weaken the effect of NT-3, while BAY 11-7082 can enhance the effect of NT-3. In short, NT-3 significantly improves sciatic nerve injury in rats, promotes sciatic nerve function repair, accelerates M2 macrophage phenotype polarization, and improves neuroinflammatory response. The protective effects of NT-3 mentioned above are partially related to the AMPK/NF-κB signal axis. [ABSTRACT FROM AUTHOR]

Alternatively activated macrophage (M2) polarization can result in one of four subtypes based on cytokines and signaling pathways associated with macrophage activation: M2a, M2b, M2c, and M2d macrophages. The majority of M2 subtypes are anti-inflammatory and pro-angiogenic, secreting growth factors (VEGF, PDGF) and matrix metalloproteinases (MMP2, MMP9) which boost tumor growth, metastasis, and invasion. M2-polarized macrophages are associated with immune suppressor cells harboring Myeloid derived suppressor cells, Regulatory T cells (Tregs), Regulatory B cells as well as alternatively activated (N2) neutrophils. Treg cells selectively support the metabolic stability, mitochondrial integrity, and survival rate of M2-like TAMs in an indirect environment. Also, the contribution of Breg cells influences macrophage polarization towards the M2 direction. TAM is activated when TAN levels in the tumor microenvironment are insufficient or vice versa, suggesting that macrophage and its polarization are fine-tuned. Understanding the functions of immune suppressive cells, mediators, and signaling pathways involved with M2 polarization will allow us to identify potential strategies for targeting the TAM repolarization phenotype for innovative immunotherapy approaches. In this review, we have highlighted the critical factors for M2 macrophage polarization, differential cytokine/chemokine profiles of M1 and M2 macrophage subtypes, and other immune cells' impact on the polarization within the immunosuppressive niche. Highlights: M2 macrophages are targetable immune cells for immunotherapy strategies. M2 type macrophages are more heterogeneous populations than M1 macrophages. M2 polarization is influenced by Tregs, Bregs, MDSCs, and N2 neutrophils. [ABSTRACT FROM AUTHOR]

Abstract Background Although the representative treatment for colorectal cancer (CRC) is radiotherapy, cancer cells survive due to inherent radioresistance or resistance acquired after radiation treatment, accelerating tumor malignancy and causing local recurrence and metastasis. However, the detailed mechanisms of malignancy induced after radiotherapy are not well understood. To develop more effective and improved radiotherapy and diagnostic methods, it is necessary to clearly identify the mechanisms of radioresistance and discover related biomarkers. Methods To analyze the expression pattern of miRNAs in radioresistant CRC, sequence analysis was performed in radioresistant HCT116 cells using Gene Expression Omnibus, and then miR-1226-5p, which had the highest expression in resistant cells compared to parental cells, was selected. To confirm the effect of miR-1226-5 on tumorigenicity, Western blot, qRT-PCR, transwell migration, and invasion assays were performed to confirm the expression of EMT factors, cell mobility and invasiveness. Additionally, the tumorigenic ability of miR-1226-5p was confirmed in organoids derived from colorectal cancer patients. In CRC cells, IRF1, a target gene of miR-1226-5p, and circSLC43A1, which acts as a sponge for miR-1226-5p, were discovered and the mechanism was analyzed by confirming the tumorigenic phenotype. To analyze the effect of tumor-derived miR-1226-5p on macrophages, the expression of M2 marker in co-cultured cells and CRC patient tissues were confirmed by qRT-PCR and immunohistochemical (IHC) staining analyses. Results This study found that overexpressed miR-1226-5p in radioresistant CRC dramatically promoted epithelial-mesenchymal transition (EMT), migration, invasion, and tumor growth by suppressing the expression of its target gene, IRF1. Additionally, we discovered circSLC43A1, a factor that acts as a sponge for miR-1226-5p and suppresses its expression, and verified that EMT, migration, invasion, and tumor growth are suppressed by circSLC43A1 in radioresistant CRC cells. Resistant CRC cells-derived miR-1226-5p was transferred to macrophages and contributed to tumorigenicity by inducing M2 polarization and secretion of TGF-β. Conclusions This study showed that the circSLC43A1/miR-1226-5p/IRF1 axis is involved in radioresistance and cancer aggressiveness in CRC. It was suggested that the discovered signaling factors could be used as potential biomarkers for diagnosis and treatment of radioresistant CRC.

Abstract Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous tumor. Commonly used tumor staging don’t sufficiently and accurately assess the prognosis of HNSCC patients, resulting in a lack of guidance for clinical treatment decisions. M2 macrophage infiltration has been shown to be strongly associated with the tumor prognosis. In this study, we used the Cancer Genome Atlas (TCGA) data to screen for genes co-expressed with M2 macrophages in HNSCC. We used univariate Cox regression to screen out the genes associated with HNSCC prognosis, and constructed a HNSCC prognosis model by Lasso regression analysis. The results confirmed that the model had good predictive value and accuracy for the prognosis of HNSCC patients by survival analysis, ROC curve and nomogram. We divided the HNSCC samples into high-risk and low-risk groups according to the risk score, and the results showed that patients in the high-risk group were more prone to genetic mutations and had a higher tumor mutational burden. In addition, there were significant differences between risk groups in terms of immune cell infiltration and drug sensitivity. The HNSCC prognostic model established in this study may provide guidance for clinical therapeutic decision-making and provide a theoretical foundation for the development of new immunotherapy methods.

Exosomes (EXOs) are important mediators of intercellular communication that contain a variety of substances, including miRNA, mRNA, DNA, and protein molecules, which can act on target cells and have broad medical prospects as “cell-free therapy”. The inclusion of EXOs varies with the type and state of the donor cell, thus EXOs from different cell types may exhibit different biological effects. Dental mesenchymal stem cell (DMSC)-derived EXOs (DMSC-EXOs) have gained increasing research attention in the fields of tissue regenerative medicine and immune regulation. Current research on EXOs is focused on the homeostasis between proinflammatory (M1)/anti-inflammatory (M2) macrophages and T-helper 17 (Th17)/regulatory T (Treg) cells during periodontal immune regulation. Studies have shown that DMSC-EXOs can promote the transformation of macrophages and T cells and that this function may be dependent on the surrounding microenvironment and the tissue origin of stem cells. For instance, miR-1246 in dental pulp stem cell-derived EXOs promotes M2 macrophage polarization by inhibiting nuclear factor kappa-B (NF-κB) p65. Meanwhile, EXOs derived from stem cells from apical papilla promote DNA demethylase Tet2-mediated demethylation of FoxP3, maintain stable FoxP3 expression, and promote Treg cell transformation, thus alleviating local inflammation in periodontitis. In addition, the immunomodulatory activities of DMSC-EXOs can be affected by inflammatory factors. For example, EXOs derived from lipopolysaccharide-preconditioned dental follicle stem cells can reduce the receptor activator of NF-κB ligand/osteoprotegerin ratio through the reactive oxygen species (ROS)/c-Jun N-terminal kinase signaling pathway and promote M2 macrophage polarization through the ROS/extracellular signal-regulated kinase signaling pathway. Additionally, EXOs derived from gingiva-derived mesenchymal stem cells pretreated with tumor necrosis factor-α and interferon-α proinflammatory cytokines can promote M2 macrophage polarization through high expression of CD73 and CD5L, while EXOs derived from inflammatory periodontal ligament stem cells can promote M1 macrophage polarization. This article reviews the research progress on the immunoregulation and effects of DMSC-EXOs on the homeostasis of M1/M2 macrophages and Th17/Treg cells during periodontal immune regulation and provides a reference for the treatment of periodontitis using DMSC-EXOs.

Abstract Background The BEAN1 gene, primarily studied in neurodegenerative diseases, has been scarcely studied in the context of cancers. Our research examines BEAN1 expression specifically in rectal adenocarcinoma (READ) and its association with prognosis, immune evasion, and chemotherapy resistance. Methods Data from TCGA and GEO were analyzed to assess BEAN1 levels across various cancer types, with particular emphasis on READ. Functional enrichment, immune infiltration, and treatment response analyses were conducted, followed by validation using patient tissue samples. Results READ tissues exhibited a marked increase in BEAN1 expression compared to normal tissues. Elevated BEAN1 levels were associated with reduced overall survival and increased immune suppression, characterized by elevated M2 macrophage infiltration and reduced CD8+ T cell presence. BEAN1 expression was also linked to higher immune checkpoint genes expression and resistance to immune checkpoint inhibitors and 5-fluorouracil. Conclusion This research offers initial evidence that BEAN1 is linked to unfavorable prognosis, immune escape, and resistance to chemotherapy in READ. BEAN1 appears to be a promising new biomarker and potential therapeutic target, warranting further investigation into its potential clinical applications in improving treatment outcomes for READ patients.

Abstract Purpose Recent studies have increasingly linked Ephrin receptor B2 (EPHB2) to cancer progression. However, comprehensive investigations into the immunological roles and prognostic significance of EPHB2 across various cancers remain lacking. Methods We employed various databases and bioinformatics tools to investigate the impact of EPHB2 on prognosis, immune infiltration, genome instability, and response to immunotherapy. Validation of the correlation between EPHB2 expression and M2 macrophages included analyses using bulk and single-cell transcriptomic datasets, spatial transcriptomics, and multi-fluorescence staining. Moreover, we performed cMap web tool to screen for EPHB2-targeted compounds and assessed their potential through molecular docking and dynamics simulations. Additionally, in vitro validation using lung adenocarcinoma (LUAD) cell lines was conducted to confirm the bioinformatics predictions about EPHB2. Results EPHB2 dysregulation was observed across multiple cancer types, where it demonstrated significant diagnostic and prognostic value. Gene Set Enrichment Analysis (GSEA) indicated that EPHB2 is involved in enhancing cellular proliferation, invasiveness of cancer cells, and modulation of the anti-cancer immune response. Furthermore, it is emerged as a pan-cancer marker for M2 macrophage infiltration, supported by integrated analyses of transcriptomics and multiple fluorescence staining. In LUAD cells, knockdown of EPHB2 expression led to a decrease in both cell proliferation and migratory activity. Conclusion EPHB2 expression may serve as a pivotal indicator of M2 macrophage infiltration, offering vital insights into tumor dynamics and progression across various cancers, including lung adenocarcinoma, highlighting its significant prognostic and therapeutic potential for further exploration.

Abstract The efficacy of immunotherapy for clear cell renal cell carcinoma (ccRCC), especially advanced ccRCC, is limited, presenting a clinical challenge. This limitation is closely tied to the immune regulation network. Understanding the heterogeneity of the tumour microenvironment (TME) is crucial for developing advanced ccRCC therapies. Using publicly available ccRCC data (scRNA-seq, bulk RNA-seq, and somatic mutation data), a multiomics study was performed to explore TME heterogeneity. Three distinct ccRCC immune subtypes were identified through combined scRNA-seq and bulk RNA-seq analysis. A prognostic model based on unique cell signalling molecules in immunosuppressive tumour subtype was validated in the TCGA and CheckMate cohorts. MDK emerged as a critical regulatory gene in the immunosuppressive subtype, predicting a poor ccRCC prognosis and a poor immunotherapy response. MDK promotes M2 macrophage polarization via the MDK-LRP1 interaction, and the inhibition of MDK suppressed M2 polarization. This study revealed the heterogeneity of the ccRCC TME and a reliable prognostic model, shedding light on the vital role of MDK in the immunosuppressive TME and paving the way for optimized ccRCC immunotherapy.

Yuan-Jie Liu,1,* Jing-Xiao Li,1,* Jie-Pin Li,1 Yi-Dou Hu,2 Zhi-Bin Ma,3 Wei Huang,1 Shen-Lin Liu,1 Xi Zou1 1Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China; 2Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China; 3Nanjing YOUMENG Biology Science and Technology Co. Ltd, Nanjing, Jiangsu, 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xi Zou; Shen-lin Liu, Email fsyy00670@njucm.edu.cn; lsljsszyy@126.comBackground: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential.Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC’s clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle.Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells’ sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1’s role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation.Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.Keywords: endoplasmic reticulum membrane complex subunit 1, catenin beta 1, tumor stemness, M2 macrophage, sorafenib resistance

Man Yang,1– 3,* Xiang Xu,4,5,* Xing-an Zhao,1,2 Yun-na Ge,1,2 Juan Qin,1 Xi-ya Wang,1,2 Hua-lei Dai,1 Ji Jia,1 Si-ming Tao1 1Department of Cardiology, The Affiliated Hospital of Yunnan University, Kunming City, Yunnan Province, People’s Republic of China; 2School of Medicine, Dali University, Dali City, Yunnan Province, People’s Republic of China; 3Department of Cardiology, The First People’s Hospital of Dali, Dali City, Yunnan Province, People’s Republic of China; 4School of Medicine, Yunnan University, Kunming City, Yunnan Province, People’s Republic of China; 5Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming City, Yunnan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Si-ming Tao, Department of Cardiology, The Affiliated Hospital of Yunnan University, No. 176, Youth Road, Kunming, Yunnan Province, 650021, People’s Republic of China, Email taosm6450@ynu.edu.cnBackground: Macrophages play a crucial role in the progression of AF, closely linked to atrial inflammation and myocardial fibrosis. However, the functions and molecular mechanisms of different phenotypic macrophages in AF are not well understood. This study aims to analyze the infiltration characteristics of atrial immune cells in AF patients and further explore the role and molecular expression patterns of M2 macrophage-related genes in AF.Methods: This study integrates single-cell and large-scale sequencing data to analyze immune cell infiltration and molecular characterization of the LAA in patients with AF, using SR as a control group. CIBERSORT assesses immune cell types in LAA tissues; WGCNA identifies signature genes; cell clustering analyzes cell types and subpopulations; cell communication explores macrophage interactions; hdWGCNA identifies M2 macrophage gene modules in AF. AF biomarkers are identified using LASSO and Random Forest, validated with ROC curves and RT-qPCR. Potential molecular mechanisms are inferred through TF-miRNA-mRNA networks and single-gene enrichment analyses.Results: Myeloid cell subsets varied considerably between the AF and SR groups, with a significant increase in M2 macrophages in the AF group. Signals of inflammation and matrix remodeling were observed in AF. M2 macrophage-related genes IGF1, PDK4, RAB13, and TMEM176B were identified as AF biomarkers, with RAB13 and TMEM176B being novel markers. A TF-miRNA-mRNA network was constructed using target genes, which are enriched in the PPAR signaling pathway and fatty acid metabolism.Conclusion: Over infiltration of M2 macrophages may be an important factor in the progression of AF. The M2 macrophage-related genes IGF1, RAB13, TMEM176B and PDK4 may regulate the progression of AF through the PPAR signaling pathway and fatty acid metabolism.Keywords: atrial fibrillation, M2 macrophage, cardiac fibrosis, inflammation, single-cell RNA-sequencing, bulk RNA-sequencing

Purpose: Recent studies have increasingly linked Ephrin receptor B2 (EPHB2) to cancer progression. However, comprehensive investigations into the immunological roles and prognostic significance of EPHB2 across various cancers remain lacking. Methods: We employed various databases and bioinformatics tools to investigate the impact of EPHB2 on prognosis, immune infiltration, genome instability, and response to immunotherapy. Validation of the correlation between EPHB2 expression and M2 macrophages included analyses using bulk and single-cell transcriptomic datasets, spatial transcriptomics, and multi-fluorescence staining. Moreover, we performed cMap web tool to screen for EPHB2-targeted compounds and assessed their potential through molecular docking and dynamics simulations. Additionally, in vitro validation using lung adenocarcinoma (LUAD) cell lines was conducted to confirm the bioinformatics predictions about EPHB2. Results: EPHB2 dysregulation was observed across multiple cancer types, where it demonstrated significant diagnostic and prognostic value. Gene Set Enrichment Analysis (GSEA) indicated that EPHB2 is involved in enhancing cellular proliferation, invasiveness of cancer cells, and modulation of the anti-cancer immune response. Furthermore, it is emerged as a pan-cancer marker for M2 macrophage infiltration, supported by integrated analyses of transcriptomics and multiple fluorescence staining. In LUAD cells, knockdown of EPHB2 expression led to a decrease in both cell proliferation and migratory activity. Conclusion: EPHB2 expression may serve as a pivotal indicator of M2 macrophage infiltration, offering vital insights into tumor dynamics and progression across various cancers, including lung adenocarcinoma, highlighting its significant prognostic and therapeutic potential for further exploration. [ABSTRACT FROM AUTHOR]

Introduction: Gliomas are the most common primary intracranial tumors, known for their high invasiveness and destructiveness. Sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC7) is present in various immune cells, especially macrophages, and significantly affects immune homeostasis and cancer cell response. However, research on the role and prognostic impact of SIGLEC7 in glioma patients is currently limited. Methods: We utilized transcriptomic data from 702 glioma patients in The Cancer Genome Atlas (TCGA) and 693 glioma patients in the Chinese Glioma Genome Atlas (CGGA), along with clinical samples we collected, to comprehensively investigate the impact of SIGLEC7 on glioma expression patterns, biological functions, and prognostic value. We focused on its role in glioma-related immune responses and immune cell infiltration and analyzed its expression at the single-cell level. Finally, we validated the role of SIGLEC7 in gliomas through tissue and cell experiments. Results: SIGLEC7 expression was significantly increased in glioma patients with malignant characteristics. Survival analysis indicated that glioma patients with high SIGLEC7 expression had significantly lower survival rates. Gene function analysis revealed that SIGLEC7 is primarily involved in immune and inflammatory responses and is strongly negatively correlated with tumor-associated immune regulation. Additionally, the expression of most immune checkpoints was positively correlated with SIGLEC7, and immune cell infiltration analysis clearly demonstrated a significant positive correlation between SIGLEC7 expression and M2 macrophage infiltration levels. Single-cell analysis, along with tissue and cell experiments, confirmed that SIGLEC7 enhances macrophage polarization towards the M2 phenotype, thereby promoting glioma invasiveness through the immunosuppressive effects of M2 macrophages. Cox regression analysis and the establishment of survival prediction models indicated that high SIGLEC7 expression is an unfavorable prognostic factor for glioma patients. Discussion: High SIGLEC7 expression predicts poor prognosis in glioma patients and is closely associated with M2 macrophages in the tumor environment. In the future, SIGLEC7 may become a promising target for glioma immunotherapy. [ABSTRACT FROM AUTHOR]

Korean mistletoe (Viscum album L. var. coloratum) is renowned for its medicinal properties, including anti-cancer and immunoadjuvant effects. This study aimed to elucidate the mechanisms by which Korean mistletoe lectin (V. album L. var. coloratum agglutinin; VCA) modulates breast cancer cell apoptosis and macrophage polarization. The specific objectives were to (1) investigate the direct effects of VCA on MCF-7 breast cancer cells and THP-1-derived M1/M2 macrophages; (2) analyze the impact of VCA on the paracrine interactions between these cell types; and (3) compare the efficacy of VCA in 2D vs. 3D co-culture models to bridge the gap between in vitro and in vivo studies. We employed both 2D and 3D models, co-culturing human M1/M2 macrophages with human MCF-7 breast cancer cells in a Transwell system. Our research demonstrated that M1 and M2 macrophages significantly influenced the immune and apoptotic responses of breast cancer cells when exposed to VCA. M1 macrophages exhibited cytotoxic characteristics and enhanced VCA-induced apoptosis in both 2D and 3D co-culture models. Conversely, M2 macrophages initially displayed a protective effect by reducing apoptosis in breast cancer cells, but this protective effect was reversed upon exposure to VCA. Furthermore, our findings illustrate VCA's ability to modulate M1 and M2 polarization in breast cancer cells. Finally, the use of magnetic 3D cell cultures suggests their potential to yield results comparable to conventional 2D cultures, bridging the gap between in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

Wound healing is facilitated by biomaterials-based grafts and substantially impacted by orchestrated inflammatory responses that are essential to the normal repair process. Tropoelastin (TE) based materials are known to shorten the period for wound repair but the mechanism of anti-inflammatory performance is not known. To explore this, we compared the performance of the gold standard Integra Dermal Regeneration Template (Integra), polyglycerol sebacate (PGS), and TE blended with PGS, in a murine full-thickness cutaneous wound healing study. Systemically, blending with TE favorably increased the F4/80+ macrophage population by day 7 in the spleen and contemporaneously induced elevated plasma levels of anti-inflammatory IL-10. In contrast, the PGS graft without TE prompted prolonged inflammation, as evidenced by splenomegaly and greater splenic granulocyte and monocyte fractions at day 14. Locally, the inclusion of TE in the graft led to increased anti-inflammatory M2 macrophages and CD4+ T cells at the wound site, and a rise in Foxp3+ regulatory T cells in the wound bed by day 7. We conclude that the TE-incorporated skin graft delivers a pro-healing environment by modulating systemic and local tissue responses. Tropoelastin (TE) has shown significant benefits in promoting the repair and regeneration of damaged human tissues. In this study, we show that TE promotes an anti-inflammatory environment that facilitates cutaneous wound healing. In a mouse model, we find that inserting a TE-containing material into a full-thickness wound results in defined, pro-healing local and systemic tissue responses. These findings advance our understanding of TE's restorative value in tissue engineering and regenerative medicine, and pave the way for clinical applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Modulating the immune microenvironment to establish sustained positive feedback within immune pathways represents a promising avenue for the treatment of autoimmunity. However, the precise and efficient delivery of therapeutic systems to the subcutaneous basal layer to modulate immune disorders is a major challenge in the treatment of autoimmune psoriasis. In this project, we introduce a dual-functional microneedle (DF-MN) designed to combine MNs with multiple release kinetics and immunotherapy, the programmed treatment is achieved through segmented design of the MN structure, realizing the unification of rapid and long-lasting treatment of autoimmune psoriasis. In vivo imaging results showed that GelMA@M-CSF showed fluorescent signals after 5 days of delivery to subcutaneous tissues, whereas HA@IL-13 showed minimal fluorescent signals after 2 days. The multistage release behavior of MNs and the diffusion mechanism of drugs were explained at the molecular level, in combination with coarse-grained molecular dynamics. Additionally, DF-MN can successfully induce macrophage reprogramming in vitro and ameliorate overall symptoms in a psoriasis mice model, suggesting that it has the potential to be an effective strategy for the treatment of psoriasis and portends to be a transformative platform for the treatment of other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Extracellular HSP90α (eHSP90α) is a promoter of tumor development and malignant progression. Patients with malignancies, including pancreatic ductal adenocarcinoma (PDAC), have generally shown 5~10-fold increases in serum/plasma eHSP90α levels. In this study, we developed a humanized antibody HH01 to target eHSP90α and evaluated its anticancer efficacy. HH01, with novel complementarity-determining regions, exhibits high binding affinity toward HSP90α. It recognizes HSP90α epitope sites 235AEEKEDKEEE244 and 251ESEDKPEIED260, with critical amino acid residues E237, E239, D240, K241, E253, and K255. HH01 effectively suppressed eHSP90α-induced invasive and spheroid-forming activities of colorectal cancer and PDAC cell lines by blocking eHSP90α's ligation with the cell-surface receptor CD91. In mouse models, HH01 potently inhibited the tumor growth of PDAC cell grafts/xenografts promoted by endothelial-mesenchymal transition-derived cancer-associated fibroblasts while also reducing serum eHSP90α levels, reflecting its anticancer efficacy. HH01 also modulated tumor immunity by reducing M2 macrophages and reinvigorating immune T-cells. Additionally, HH01 showed low aggregation propensity, high water solubility, and a half-life time of >18 days in mouse blood. It was not cytotoxic to retinal pigmented epithelial cells and showed no obvious toxicity in mouse organs. Our data suggest that targeting eHSP90α with HH01 antibody can be a promising novel strategy for PDAC therapy. [ABSTRACT FROM AUTHOR]

Gastric cancer, the fifth most prevalent cancer worldwide, is often diagnosed in advanced stages with limited treatment options. Examining the tumor microenvironment (TME) and its metabolic reprogramming can provide insights for better diagnosis and treatment. This study investigates the link between TME factors and metabolic activity in gastric cancer using bulk and single-cell RNA-sequencing data. We identified two molecular subtypes in gastric cancer by analyzing the distinct expression patterns of 81 prognostic genes related to the TME and metabolism, which exhibited significant protein-level interactions. The high-risk subtype had increased stromal content, fibroblast and M2 macrophage infiltration, elevated glycosaminoglycans/glycosphingolipids biosynthesis, and fat metabolism, along with advanced clinicopathological features. It also exhibited low mutation rates and microsatellite instability, associating it with the mesenchymal phenotype. In contrast, the low-risk group showed higher tumor content and upregulated protein and sugar metabolism. We identified a 15-gene prognostic signature representing these characteristics, including CPVL, KYNU, CD36, and GPX3, strongly correlated with M2 macrophages, validated through single-cell analysis and an internal cohort. Despite resistance to immunotherapy, the high-risk group showed sensitivity to molecular targeted agents directed at IGF-1R (BMS-754807) and the PI3K-mTOR pathways (AZD8186, AZD8055). We experimentally validated these promising drugs for their inhibitory effects on MKN45 and MKN28 gastric cells. This study unveils the intricate interplay between TME and metabolic pathways in gastric cancer, offering potential for enhanced diagnosis, patient stratification, and personalized treatment. Understanding molecular features in each subtype enriches our comprehension of gastric cancer heterogeneity and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Extracellular vesicles called exosomes are primarily used as mediators of intercellular signal transmission to control tumor metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with exosome generation in chondrosarcoma motility remains undetermined. Our results found that overexpressing visfatin augments the production of exosomes from chondrosarcoma cells. Visfatin‐treated chondrosarcoma exosomes educate macrophage polarization towards the M2 but not M1 phenotype. Interestingly, M2 macrophages polarized by exosomes return to chondrosarcoma cells to facilitate cell motility. According to these findings, chondrosarcoma cells emit more exosomes when treated with visfatin. The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common invasive cancer in women. M2 macrophage exosomes promote cancer development and play multiple roles in the tumor microenvironment, but the mechanism of action by which M2 macrophage exosomes promote BC remains unclear. Therefore, the purpose of this study was to investigate the mechanism by which M2 macrophage-derived exosomes promote the development of breast cancer. We collected BC tissues and determined the expression of LINC00470, followed by the establishment of M2 macrophages in culture and the isolation and identification of M2 macrophage exosomes. Next, we investigated the effects of M2 macrophage exosomes on BC cell proliferation, invasion, miR-199a-3p promoter methylation, and the expression of LINC00470, myc, DNMT3A, and miR-199a-3p. Finally, LINC00470 expression was inhibited in M2 macrophage exosomes, while miR-199a-3p expression was inhibited in BC cells, and changes in BC cell proliferation, invasion, miR-199a-3p promoter methylation, and the expression of LINC00470, myc, DNMT3A, and miR-199a-3p were analyzed. We demonstrated that LINC00470 was highly expressed in BC tissues, M2-type macrophages were successfully induced in vitro, and Dil-labeled M2 macrophage exosomes could successfully enter MDA-MB-231 and MCF-7 cells. Coculture of M2 macrophage exosomes with MDA-MB-231 and MCF-7 cells significantly enhanced the proliferation and invasion of MDA-MB-231 and MCF-7 cells, upregulated the expression of LINC00470, myc, and DNMT3A and downregulated the expression of miR-199a-3p. Moreover, the inhibition of LINC00470 expression in M2 macrophage exosomes significantly downregulated the expression of LINC00470, myc, and DNMT3A in MDA-MB-231 and MCF-7 cells, upregulated the expression of miR-199a-3p, and hypomethylated the promoter of the miR-199a-3p locus. Moreover, inhibition of LINC00470 expression in M2 macrophage-derived exosomes significantly attenuated the proliferation and invasive ability of MDA-MB-231 and MCF-7 cells, while miR-199a-3p inhibitor transfection reversed this effect. Collectively, these findings indicated that M2-type macrophage-derived exosomes promote BC proliferation and migration by regulating miR-199a-3p promoter methylation through the LINC00470-mediated myc/DNMT3a axis. [ABSTRACT FROM AUTHOR]

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis.

Objectives: Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer (BC). Tumor-derived extracellular vesicles (EVs) trigger tumor progression by promoting M2 polarization. Some lncRNAs can be encapsulated into EVs for intercellular communication. Herein, we investigated the mechanism of TNBC-derived EV-shuttled lncRNA MALAT1 on macrophage polarization/tumorigenesis. Methods: BC-associated targeted EV-derived lncRNAs were screened. Tumor tissues/tissues adjacent to cancer of TNBC patients, and blood samples of all subjects were collected. MALAT1/POSTN mRNA levels in tumor tissues/tissues adjacent to cancer, and MALAT1 expression in EVs and its correlation with TNBC patient overall survival were assessed by RT-qPCR/Kaplan-Meier survival analysis/log-rank test. TNBC patient M2 infiltration was detected by flow cytometry. MALAT1/POSTN levels in EVs/macrophages were regulated by transfection. Hippo/YAP activation was determined by Western blot. Nude mouse xenograft model was established and metastasis was detected by H&E staining. Results: MALAT1/POSTN were up-regulated and correlated with M2 infiltration/poor prognosis in TNBC patients. TNBC-derived EVs induced M2 polarization. MALAT1 was highly expressed in TNBC-derived EVs and could be transferred to macrophages via EVs to induce M2 polarization. POSTN overexpression diminished the inhibitory effect of MALAT1 knockdown on M2 markers. EVs activated the Hippo/YAP pathway in macrophages. The Hippo/YAP pathway inhibition abrogated the effect of POSTN overexpression on M2 marker expression. TNBC-EV-derived MALAT1 facilitated M2 polarization, and thus promoting occurrence and metastasis of TNBC in vitro and in vivo. Conclusions: TNBC-EV-derived MALAT1 activated the Hippo/YAP axis by up-regulating POSTN, thereby inducing M2 polarization to promote TNBC occurrence and metastasis in vivo.

The development of novel phototheranostic agents with significant potential in bioimaging-guided therapy is highly desirable for precise tumor therapy. Herein, NIR laser-activated ruthenium phthalocyanine (PcRu) loaded sub-30 nm targeting lipid nanoparticles (α-PcRu-NPs) were fabricated for photoacoustic imaging (PAI)-guided photothermal therapy (PTT). Due to the formation of J-type aggregation of PcRu in the core of the nanostructure, the α-PcRu-NPs exhibited high stability, efficient NIR absorption, reduced singlet oxygen generation, high photothermal activity, and intense photoacoustic signal. With the M2 macrophage target peptide (M2pep) modification and small size of α-PcRu-NPs, in vivo evaluations reveal that α-PcRu-NPs can specifically target and deeply penetrate the tumor foci. Under a high contrast PAI guidance with α-PcRu-NPs (744 nm, 0.35 μW), it also realizes superior photothermal therapy (PTT) for breast cancer under 670 nm laser irradiation (0.5 W/cm2). The prominent therapeutic efficacy of α-PcRu-NP-based PTT not only directly kills tumor cells, but also enhances the immune response by promoting dendritic cell maturation and increasing cytotoxic T cell infiltration. Thus, this work broadens the applications of phthalocyanine derivatives as phototheranostics in the PAI-guided PTT field.

Idiopathic pulmonary fibrosis is a progressive lung disease characterized by excessive extracellular matrix accumulation and myofibroblast proliferation with limited treatment options available. M2 macrophages are pivotal in pulmonary fibrosis, where they induce the epithelial-to-mesenchymal and fibroblast-to-myofibroblast transitions. In this study, we evaluated whether MEL-dKLA, a hybrid peptide that can eliminate M2 macrophages, could attenuate pulmonary fibrosis in a cell co-culture system and in a bleomycin-induced mouse model. Our findings demonstrated that the removal of M2 macrophages using MEL-dKLA stimulated reprogramming to an antifibrotic environment, which effectively suppressed epithelial-to-mesenchymal and fibroblast-to-myofibroblast transition responses in lung epithelial and fibroblast cells and reduced extracellular matrix accumulation both in vivo and in vitro. Moreover, MEL-dKLA exhibited antifibrotic efficacy without damaging tissue-resident macrophages in the bleomycin-induced mouse model. Collectively, our findings suggest that MEL-dKLA may be a new therapeutic option for the treatment of idiopathic pulmonary fibrosis.

Adipose tissue-resident macrophages (ATMs) are reported to be important for maintaining adipose tissue remodeling and homeostasis. ATMs were classified for the first time in 2007 into the M1 and M2 types. This theory suggests that in the non-obese adipose tissue, the anti-inflammatory, alternatively activated macrophages (AAMs) predominate, and regulate tissue homeostasis, remodeling, and insulin sensitivity. On the other hand, classically activated M1-type macrophages increase rapidly in obesity, secrete inflammatory cytokines, such as TNFα and IL-6, and induce insulin resistance. In recent years, experimental findings that cannot be explained by this theory have been clarified one after another and the theory is being reconsidered. In this review, based on recent findings, we summarize reports on the novel metabolic regulatory functions of ATMs beyond the M1/M2 paradigm.

Xiangwen Shi,1,2,* Haonan Ni,3,* Linmeng Tang,4,* Mingjun Li,2 Yipeng Wu,2 Yongqing Xu3 1Graduate School, Kunming Medical University, Kunming, People’s Republic of China; 2Laboratory of Yunnan Traumatology and Orthopedics Clinical Medical Center, Yunnan Orthopedics and Sports Rehabilitation Clinical Medical Research Center, Department of Orthopedic Surgery, 920th Hospital of Joint Logistics Support Force of PLA, Kunming, People’s Republic of China; 3First People’s Hospital of Huzhou, the First affiliated Hospital of Huzhou University, Huzhou, People’s Republic of China; 4Department of Radiology, the Second Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongqing Xu, Department of Orthopedic Surgery, 920th Hospital of Joint Logistics Support Force, 212 Daguan Road, Xi Shan District, Kunming, Yunnan, 650031, People’s Republic of China, Email xuyongqingkm@163.net Yipeng Wu, Department of Orthopedic Surgery, 920th Hospital of Joint Logistics Support Force, 212 Daguan Road, Xi Shan District, Kunming, Yunnan, 650031, People’s Republic of China, Email 20201497@kmmu.edu.cnObjective: Osteomyelitis is a challenging disease in the field of bone infections, with its immune and molecular regulatory mechanisms still poorly understood. The aim of this study is to explore the value and potential mechanisms of cuproptosis-related genes (CRGs) in Staphylococcus aureus (S. aureus)-infected osteomyelitis from an immunological perspective.Methods: Initially, three transcriptomic datasets from public databases were integrated and analyzed, and consistent expression of CRGs in S. aureus-infected osteomyelitis was identified. Subsequently, immune infiltration analysis was performed, and M2 macrophage-related CRGs (M2R-CRGs) were further identified. Their potential molecular mechanisms were evaluated using Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA). Finally, distinct osteomyelitis subtypes and diagnostic models based on characteristic M2R-CRGs were constructed.Results: Through correlation analysis with immune cell infiltration, three characteristic M2R-CRGs (SLC31A1, DLD, and MTF1) were identified. Further analysis using unsupervised clustering and immune microenvironment analysis indicated that cluster 1 might activate pro-inflammatory responses, while cluster 2 was shown to exhibit anti-inflammatory effects in osteomyelitis. Compared to Cluster A, Cluster B demonstrated higher levels and a greater diversity of immune cell infiltrations in CRG-related molecular patterns, suggesting a potential anti-inflammatory role in osteomyelitis. A diagnostic model for S. aureus-infected osteomyelitis, based on the three M2R-CRGs, was constructed, exhibiting excellent diagnostic performance and validated with an independent dataset. Significant upregulation in mRNA and protein expression levels of the three M2R-CRGs was observed in rat models of S. aureus-infected osteomyelitis, aligning with bioinformatic results.Conclusion: The M2R-CRGs (SLC31A1, DLD, and MTF1) may be considered characteristic genes for early diagnosis and personalized immune therapy in patients with S. aureus-infected osteomyelitis.Keywords: osteomyelitis, cuproptosis, Staphylococcus aureus, M2 macrophage, immune infiltration, diagnosis

Atherosclerosis is featured as chronic low-grade inflammation in the arteries, which leads to the formation of plaques rich in lipids. M2 macrophage-derived extracellular vesicles (M2EV) have significant potential for anti-atherosclerotic therapy. However, their therapeutic effectiveness has been hindered by their limited targeting capability in vivo. The objective of this study was to create the P-M2EV (platelet membrane-modified M2EV) using the membrane fusion technique in order to imitate the interaction between platelets and macrophages. P-M2EV exhibited excellent physicochemical properties, and microRNA (miRNA)-sequencing revealed that the extrusion process had no detrimental effects on miRNAs carried by the nanocarriers. Remarkably, miR-99a-5p was identified as the miRNA with the highest expression level, which targeted the mRNA of Homeobox A1 (HOXA1) and effectively suppressed the formation of foam cells in vitro. In an atherosclerotic low-density lipoprotein receptor-deficient (Ldlr−/−) mouse model, the intravenous injection of P-M2EV showed enhanced targeting and greater infiltration into atherosclerotic plaques compared to regular extracellular vesicles. Crucially, P-M2EV successfully suppressed the progression of atherosclerosis without causing systemic toxicity. The findings demonstrated a biomimetic platelet-mimic system that holds great promise for the treatment of atherosclerosis in clinical settings.

Macrophages have strong plasticity and heterogeneity, and can undergo functional transformation in response to different signal stimuli, such as classical activation of M1 type (M1 type polarization) and selective activation of M2 type (M2 type polarization). The pathways of macrophage M1/M2 polarization are quite extensive, involving nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, interleukin-4 (IL-4)/signal transduction and activator of transcription 6 (STAT6) signaling pathway, Notch signaling pathway, Wnt/β-catenin signaling pathway, etc. At the same time, M1/M2 polarization of macrophages is also regulated by exosomes, metabolites, non-coding RNA, electrical stimulation, probiotics, etc., and its imbalance is closely related to the occurrence and development of different types of liver disease. In this paper, the mechanism of its polarization was reviewed, and it was found that M1 polarization of macrophages played a promoting role in the process of liver tissue injury, inflammation and fibrosis, while M2 polarization of macrophages played the opposite role. Among them, hepatocellular carcinoma, as the advanced stage of chronic liver disease, was characterized by increased M2 polarization and impaired M1 polarization of macrophages. Therefore, this paper pays attention to the role of M1/M2 polarization of macrophages in different types of liver diseases, in order to better establish the targeted therapy of macrophage subsets.

Background Idiopathic Pulmonary Fibrosis (IPF) presents a severe respiratory challenge with a poor prognosis due to the lack of reliable biomarkers. Recent evidence suggests that Endoplasmic Reticulum Stress (ERS) may be associated with IPF pathogenesis. This study focuses on uncovering ERS-associated biomarkers for IPF.Methods Sequencing data from diverse datasets were analyzed, utilizing differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Endoplasmic Reticulum Stress (ERS)-related genes were extracted from the GeneCards database. Hub genes were identified through Protein-Protein Interaction (PPI) analysis. Diagnostic and prognostic models were developed using machine learning algorithms and validated across both training and validation sets. Additionally, techniques such as Cell-type Identification by Estimating Relative Subsets of RNA Transcripts and single-cell RNA sequencing were employed to identify potential IPF-related cells. These findings were further investigated to elucidate their underlying mechanisms through in vitro experiments.Results Differentially expressed genes, WGCNA-identified blue module genes, and ERS-related genes extracted from the GeneCards database were intersected, and the resulting genes were used to construct diagnostic and prognostic models. Validation using multiple datasets indicated that both the diagnostic and prognostic models possess strong predictive capabilities. PPI analysis highlighted SPP1 as a potential hub gene in IPF. Moreover, M2 macrophages were found in higher quantities in the lung tissue of IPF patients, with a significant increase in SPP1-expressing M2 macrophages compared to the control group. In vitro experiments demonstrated that exogenous SPP1 inhibited the proliferation and migration of M2 macrophages and promoted apoptosis within a certain concentration range.Conclusion This study identifies ERS-related biomarkers in IPF, highlighting SPP1 and M2 macrophages. The resulting diagnostic and prognostic models offer strong predictive capabilities, unveiling new therapeutic avenues.

Aflatoxin B1 (AFB1) contamination in food and feed leads to severe global health problems. Acting as the frontier immunological barrier, the intestinal mucosa is constantly challenged by exposure to foodborne toxins such as AFB1 via contaminated diets, but the detailed toxic mechanism and endogenous regulators of AFB1 toxicity are still unclear. Here, we showed that AFB1 disrupted intestinal immune function by suppressing macrophages, especially M2 macrophages, and antimicrobial peptide-secreting Paneth cells. Using an oxylipinomics approach, we identified that AFB1 immunotoxicity is associated with decreased epoxy fatty acids, notably epoxyeicosatrienoic acids, and increased soluble epoxide hydrolase (sEH) levels in the intestine. Furthermore, sEH deficiency or inhibition rescued the AFB1-compromised intestinal immunity by restoring M2 macrophages as well as Paneth cells and their-derived lysozyme and α-defensin-3 in mice. Altogether, our study demonstrates that AFB1 exposure impairs intestinal immunity, at least in part, in a sEH-mediated way. Moreover, the present study supports the potential application of pharmacological intervention by inhibiting the sEH enzyme in alleviating intestinal immunotoxicity and associated complications caused by AFB1 global contamination.

Cancer remains a significant challenge for public healthcare systems worldwide. Within the realm of cancer treatment, considerable attention is focused on understanding the tumor microenvironment (TME)—the complex network of non-cancerous elements surrounding the tumor. Among the cells in TME, tumor-associated macrophages (TAMs) play a central role, traditionally categorized as pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Within the TME, M2-like TAMs can create a protective environment conducive to tumor growth and progression. These TAMs secrete a range of factors and molecules that facilitate tumor angiogenesis, increased vascular permeability, chemoresistance, and metastasis. In response to this challenge, efforts are underway to develop adjuvant therapy options aimed at reprogramming TAMs from the M2 to the anti-tumor M1 phenotype. Such reprogramming holds promise for suppressing tumor growth, alleviating chemoresistance, and impeding metastasis. Nanotechnology has enabled the development of nanoformulations that may soon offer healthcare providers the tools to achieve targeted drug delivery, controlled drug release within the TME for TAM reprogramming and reduce drug-related adverse events. In this review, we have synthesized the latest data on TAM polarization in response to TME factors, highlighted the pathological effects of TAMs, and provided insights into existing nanotechnologies aimed at TAM reprogramming and depletion. [ABSTRACT FROM AUTHOR]

Oestrogen is known to be strongly associated with ovarian cancer. There was much work to show the importance of lncRNA SNHG17 in ovarian cancer. However, no study has revealed the molecular regulatory mechanism and functional effects between oestrogen and SNHG17 in the development and metastasis of ovarian cancer. In this study, we found that SNHG17 expression was significantly increased in ovarian cancer and positively correlated with oestrogen treatment. Oestrogen could promote M2 macrophage polarization as well as ovarian cancer cells SKOV3 and ES2 cell exosomal SNHG17 expression. When exposure to oestrogen, exosomal SNHG17 promoted ovarian cancer cell proliferation, migration, invasion and epithelial‐mesenchymal transition (EMT) in vitro, and tumour growth and lung metastasis in vivo by accelerating M2‐like phenotype of macrophages. Mechanically, exosomal SNHG17 could facilitate the release of CCL13 from M2 macrophage via the PI3K‐Akt signalling pathway. Moreover, CCL13‐CCR2 axis was identified to be involved in ovarian cancer tumour behaviours driven by oestrogen. There results demonstrate a novel mechanism that exosomal SNHG17 exerts an oncogenic effect on ovarian cancer via the CCL13–CCR2–M2 macrophage axis upon oestrogen treatment, of which SNHG17 may be a potential biomarker and therapeutic target for ovarian cancer responded to oestrogen. [ABSTRACT FROM AUTHOR]

Platelets and M2 macrophages both play crucial roles in tumorigenesis, but their relationship and the prognosis value of the relative genes in bladder cancer (BLCA) remain obscure. In the present study, we found that platelets stimulated by BLCA cell lines could promote M2 macrophage polarization, and platelets were significantly associated with the infiltration of M2 macrophages in BLCA samples. Through the bioinformatic analyses, A2M, TGFB3, and MYLK, which were associated with platelets and M2 macrophages, were identified and verified in vitro and then included in the predictive model. A platelet and M2 macrophage‐related gene signature was constructed to evaluate the prognosis and immunotherapeutic sensitivity, helping to guide personalized treatment and to disclose the underlying mechanisms. [ABSTRACT FROM AUTHOR]

The unpredictable survival rate of autologous fat grafting (AFG) seriously affects its clinical application. Improving the survival rate of AFG has become an unresolved issue in plastic surgery. Peroxisome proliferator-activated receptor-γ (PPAR-γ) regulates the adipogenic differentiation of adipocytes, but the functional mechanism in AFG remains unclear. In this study, we established an animal model of AFG and demonstrated the superior therapeutic effect of PPAR-γ regulation in the process of AFG. From day 3 after fat grafting, the PPAR-γ agonist rosiglitazone group consistently showed better adipose integrity, fewer oil cysts, and fibrosis. Massive macrophage infiltration was observed after 7 days. At the same time, M2 macrophages begin to appear. At day 14, M2 macrophages gradually became the dominant cell population, which suppressed inflammation and promoted revascularization and fat regeneration. In addition, transcriptome sequencing showed that the differentially expressed genes in the Rosiglitazone group were associated with the pathways of adipose regeneration, differentiation, and angiogenesis; these results provide new ideas for clinical treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of M2 macrophages on the proliferation, migration and invasion of gallbladder carcinoma cells by regulating the expression of interleukin-10 (IL-10). Methods: Human monocyte line THP-1 was induced into M2 macrophages in vitro, and the expression of corresponding markers and IL-10 was detected by RT-qPCR. The expression of IL-10 in cell supernatant was detected by ELISA. GBC cell lines NOZ and GBC-SD were divided into the Control group (serum-free medium), the M2-CM group (M2 macrophage conditioned medium), the M2-CM+anti-IL-10 group (M2-CM containing anti-IL-10) and the M2-CM + IgG group (M2-CM containing IL-10 isotype control antibody). The cell proliferation rate of each group was measured by CCK-8 test, the cell migration rate of each group was detected by cell scratch test and the change in cell invasive ability of each group was detected by Transwell test; and Western blot assay was used to detect the expression of epithelial-mesenchymal transformation markers (E-cadherin and Vimentin) in each group. Results: M2 macrophages were successfully induced in vitro. Compared with uninduced THP-1, IL-10 was highly expressed in M2 macrophages and M2 macrophages supernatant (P<0.05). M2 macrophages could promote the proliferation, migration and invasion of GBC cells, as well as inhibit the expression of E-cadherin and promote the expression of Vimentin. Blocking IL-10 could inhibit the effect of M2 macrophages (P<0.05) . Conclusion: M2 macrophages can promote the proliferation, migration, invasion and epithelial-mesenchymal transformation of GBC cells by secreting IL-10. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer is a common malignant tumor in the female. Interleukin (IL)-17A is a proinflammatory factor and exerts a vital function in inflammatory diseases and cancers. M2 macrophage has been confirmed to promote tumor development. Nevertheless, it is not yet known whether IL-17A facilitates cervical cancer development by inducing M2 macrophage polarization. Therefore, this study was conducted to investigate the regulatory effect of IL-17A on M2 macrophage polarization and the underlying mechanism in cervical cancer development. Methods: RT-qPCR was utilized for testing IL-17A expression in cancer tissues and cells. Flow cytometry was applied to evaluate the M1 or M2 macrophage polarization. Cell proliferative, migratory, and invasive capabilities were measured through colony formation and transwell assays. ChIP and luciferase reporter assays were applied to determine the interaction between IL-17A and octamer-binding transcription factor 4 (OCT4). Results: IL-17A expression and concentration were high in metastatic tissues and cells of cervical cancer. IL-17A was found to facilitate M2 macrophage polarization in cervical cancer. Furthermore, IL-17A facilitated the macrophage-mediated promotion of cervical cancer cell proliferative, migratory, and invasive capabilities. Mechanistic assays manifested that Oct4 binds to and transcriptionally activated IL-17A in cervical cancer cells. Furthermore, Oct4 promoted cervical cancer cell malignant phenotype and M2 macrophage polarization by activating the p38 pathway that, in turn, upregulated IL-17A. Additionally, in vivo experiments confirmed that Oct4 knockdown reduced tumor growth and metastasis. Conclusion: Oct4 triggers IL-17A to facilitate the polarization of M2 macrophages, which promotes cervical cancer cell metastasis. [ABSTRACT FROM AUTHOR]

Macrophages have strong plasticity and heterogeneity, and can undergo functional transformation in response to different signal stimuli, such as classical activation of M1 type (M1 type polarization) and selective activation of M2 type (M2 type polarization). The pathways of macrophage M1/M2 polarization are quite extensive, involving nuclear factor-κB (NF-κB)/mitogenactivated protein kinase (MAPK) signaling pathway, interleukin-4 (IL-4)/signal transduction and activator of transcription 6 (STAT6) signaling pathway, Notch signaling pathway, Wnt/β-catenin signaling pathway, etc. At the same time, M1/M2 polarization of macrophages is also regulated by exosomes, metabolites, non-coding RNA, electrical stimulation, probiotics, etc., and its imbalance is closely related to the occurrence and development of different types of liver disease. In this paper, the mechanism of its polarization was reviewed, and it was found that M1 polarization of macrophages played a promoting role in the process of liver tissue injury, inflammation and fibrosis, while M2 polarization of macrophages played the opposite role. Among them, hepatocellular carcinoma, as the advanced stage of chronic liver disease, was characterized by increased M2 polarization and impaired M1 polarization of macrophages. Therefore, this paper pays attention to the role of M1/M2 polarization of macrophages in different types of liver diseases, in order to better establish the targeted therapy of macrophage subsets. [ABSTRACT FROM AUTHOR]

Atherosclerosis is the most common cause of cardiovascular diseases that contribute to the major morbidity worldwide, but still lacking of effective treatment strategy. Here, a hybrid cell is constructed for the sonodynamic effect promoted cell therapy of early atherosclerosis by fusing M2 macrophages with thylakoid (TK) membranes. After systemic administration, the obtained TK-M2 actively accumulates in the early atherosclerotic plaques, wherein M2 macrophages relieve the cholesterol accumulation and the inflammation in the foam cells. Meanwhile, the TK membranes decorated on the M2 macrophages exhibit both type I and type II sonodynamic effects under ultrasound (US) activation, inducing the direct apoptosis of foam cells. The cooperation of M2 and TK leads to significant outcome in eliminating atherosclerotic plaques without obvious side-effects, providing a new avenue for atherosclerosis treatment. [ABSTRACT FROM AUTHOR]

Heart failure remains a global threaten to public health, cardiac fibrosis being a crucial event during the development and progression of heart failure. Reportedly, M2 macrophages might affect endothelial cell (ECs) and fibroblast proliferation and functions through paracrine signaling, participating in myocardial fibrosis. In this study, differentially expressed paracrine factors between M0/1 and M2 macrophages were analyzed and the expression of TNFSF13 was most significant in M2 macrophages. Culture medium (CM) of M2 (M2 CM) coculture to ECs and cardiac fibroblasts (CFbs) significantly promoted the cell proliferation of ECs and CFbs, respectively, and elevated α-smooth muscle actin (α-SMA), collagen I, and vimentin levels within both cell lines; moreover, M2 CM-induced changes in ECs and CFbs were partially abolished by TNFSF13 knockdown in M2 macrophages. Lastly, the NF-κB and Akt signaling pathways were proved to participate in TNFSF13-mediated M2 CM effects on ECs and CFbs. In conclusion, TNFSF13, a paracrine factor upregulated in M2 macrophages, could mediate the promotive effects of M2 CM on EC and CFb proliferation and fibrogenic alterations. [ABSTRACT FROM AUTHOR]

Lymphatic vessels have been increasingly appreciated in the context of immunology not only as passive conduits for immune and cancer cell transport but also as key in local tissue immunomodulation. Targeting lymphatic vessel growth and potential immune regulation often takes advantage of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling to manipulate lymphatic biology. A receptor tyrosine kinase, VEGFR- 3, is highly expressed on lymphatic endothelial cells, and its signaling is key in lymphatic growth, development, and survival and, as a result, often considered to be "lymphatic-specific" in adults. A subset of immune cells, notably of the monocyte-derived lineage, have been identified to express VEGFR-3 in tissues from the lung to the gut and in conditions as varied as cancer and chronic kidney disease. These VEGFR-3+ macrophages are highly chemotactic toward the VEGFR-3 ligands VEGF-C and VEGF-D. VEGFR-3 signaling has also been implicated in dictating the plasticity of these cells from pro-inflammatory to anti-inflammatory phenotypes. Conversely, expression may potentially be transient during monocyte differentiation with unknown effects. Macrophages play critically important and varied roles in the onset and resolution of inflammation, tissue remodeling, and vasculogenesis: targeting lymphatic vessel growth and immunomodulation by manipulating VEGFR-3 signaling may thus impact macrophage biology and their impact on disease pathogenesis. This mini review highlights the studies and pathologies in which VEGFR-3+ macrophages have been specifically identified,aswellastheactivityand polarization changes that macrophage VEGFR-3 signaling may elicit, and affords some conclusions as to the importance of macrophage VEGFR-3 signaling in disease. [ABSTRACT FROM AUTHOR]

Koi herpesvirus (KHV, CyHV-3) causes severe economic losses in carp farms. Its eradication is challenging due to the establishment of latency in blood leukocytes and other tissues. To understand the molecular mechanisms leading to KHV infection in leukocytes, common carp were bath-exposed to KHV at 17 °C. After confirming the presence of viral transcripts in blood leukocytes at ten days post infection, RNA-Seq was performed on peripheral blood leukocytes on the Illumina NovaSeq. KHV infection triggered a robust immune response mediated by pattern recognition receptors, mainly toll-like receptors (tlr2, tlr5, tlr7, and tlr13), urokinase plasminogen activator surface receptor-like, galectin proteins, and lipid mediators such as leukotriene B4 receptor 1. Enriched pathways showed increased mitochondria oxidative phosphorylation and the activation of signalling pathways such as mitogen-activated protein kinases (MAPKs) and vascular endothelial growth factor (VEGF). KHV-infected leukocytes showed low production of reactive oxygen species (ROS) and glutathione metabolism, high iron export and phagocytosis activity, and low autophagy. Macrophage polarization was deduced from the up-regulation of genes such as arginase non-hepatic 1-like, macrophage mannose receptor-1, crem, il-10, and il-13 receptors, while markers for cytotoxic T cells were observed to be down-regulated. Further work is required to characterise these leukocyte subsets and the molecular events leading to KHV latency in blood leukocytes. [ABSTRACT FROM AUTHOR]