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The formation and accumulation of foam cells within the arterial wall is the main early event of atherosclerosis. Vascular smooth muscle cells (VSMCs) are the most abundant cells in human atherosclerotic lesions and are suggested to contribute to atheroma foam cells. γ‐glutamylcysteine (γ‐GC), as an immediate precursor of glutathione, exhibits anti‐inflammatory and antioxidant effects. However, the effects of γ‐GC on the formation of atherosclerotic plaques are not yet clarified. Here, we display the effects of γ‐GC against ox‐LDL‐induced formation of foamy VSMCs. Our results showed that γ‐GC apparently reduced the total intracellular cholesterol content in mouse and rat VSMCs. The oil red O and fluorescent BODIPY staining indicated that γ‐GC inhibited the formation of foam cell. Mechanistically, γ‐GC reduced the expression of macrophage scavenger receptor 1 (Msr1) in VSMCs to attenuate cholesterol uptake by the cells. Further RNA‐seq analysis, and immunofluorescence as well as immunoblotting measurements showed that thioredoxin‐1 (Txn1) was important for γ‐GC to reduce Msr1 expression in VSMCs and lipid uptake by the cells. Overall, our research indicated that γ‐GC increases Txn1 expression, which causes scavenger receptor A reduction and lipid uptake inhibition in ox‐LDL‐stimulated VSMCs. Our study revealed that γ‐GC has potential for the prevention of atherosclerosis. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is a disease characterized by the excessive accumulation of fat. Concurrently, thyroid carcinoma (THCA) stands as the foremost endocrine malignancy. Despite the observed escalation in concurrent prevalence of both conditions, the underlying interconnections remain elusive. This indicates the need to identify potential biomarkers to predict the pathways through which obesity and THCA coexist. Methods: The study employed a variety of methods, including differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and gene enrichment analysis. It was also supplemented with immunohistochemical data from the Human Protein Atlas (HPA), advanced machine learning techniques, and related experiments such as qPCR, to identify important pathways and key genes shared between obesity and THCA. Results: Through differential gene expression analysis, WGCNA, and machine learning methods, we identified three biomarkers (IL6R, GZMB, and MSR1) associated with obesity. After validation analysis using THCA-related datasets and biological experiments, we selected Macrophage Scavenger Receptor 1 (MSR1) as a key gene for THCA analysis. The final analysis revealed that MSR1 is closely related to the degree of immune cell infiltration in patients with obesity and THCA, suggesting that this gene may be a potential intervention target for both obesity and THCA. Discussion: Our research indicates that MSR1 may influence the occurrence and development of obesity and THCA by regulating the infiltration level of immune cells. This lays the foundation for future research on targeted therapies based on their shared mechanisms. [ABSTRACT FROM AUTHOR]

IntroductionObesity is a disease characterized by the excessive accumulation of fat. Concurrently, thyroid carcinoma (THCA) stands as the foremost endocrine malignancy. Despite the observed escalation in concurrent prevalence of both conditions, the underlying interconnections remain elusive. This indicates the need to identify potential biomarkers to predict the pathways through which obesity and THCA coexist.MethodsThe study employed a variety of methods, including differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and gene enrichment analysis. It was also supplemented with immunohistochemical data from the Human Protein Atlas (HPA), advanced machine learning techniques, and related experiments such as qPCR, to identify important pathways and key genes shared between obesity and THCA.ResultsThrough differential gene expression analysis, WGCNA, and machine learning methods, we identified three biomarkers (IL6R, GZMB, and MSR1) associated with obesity. After validation analysis using THCA-related datasets and biological experiments, we selected Macrophage Scavenger Receptor 1 (MSR1) as a key gene for THCA analysis. The final analysis revealed that MSR1 is closely related to the degree of immune cell infiltration in patients with obesity and THCA, suggesting that this gene may be a potential intervention target for both obesity and THCA.DiscussionOur research indicates that MSR1 may influence the occurrence and development of obesity and THCA by regulating the infiltration level of immune cells. This lays the foundation for future research on targeted therapies based on their shared mechanisms.

Purpose: To investigate some potential therapeutic agents and targets for nasopharyngeal carcinoma (NPC). Methods: Some potential therapeutic agents and target genes for NPC were identified by integrating bioinformatic analysis and in vitro experimental validation. Three datasets of NPC patients were gathered to reveal 26 upregulated and 344 downregulated differentially expressed genes (DGEs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analysis (KEGG) of the DGEs were implemented. Separately, 316 drug and small molecule target genes were acquired from the SEA database, allowing for detection of C6-ceramide as a small molecule of high relevance to NPC. Then, the differentially upregulated genes were intersected with potential target genes of C6-ceramide small molecules to obtain macrophage scavenger receptor 1 (MSR1). Finally, the study validated the potential roles of MSR1 and C6-ceramide in NPC cell lines. Results: Knockdown of MSR1 expressions in NPC cells significantly decreased cell viability. Treatment with 10 µmol/L C6-ceramide also significantly reduced NPC cell viability (p < 0.0001). Furthermore, C6- ceramide attenuated the increase in MSR1 levels induced by MSR1 overexpression in NPC cells (p < 0.0001). Concurrently, MSR1 knockdown decreased expression of PI3K and AKT, while MSR1 overexpression upregulated AKT and PI3K levels. Conclusion: MSR1 modulates viability of NPC cells by regulating PI3K and AKT expression. Additionally, C6-ceramide exerts therapeutic effect on NPC by regulating MSR1 expression. These findings reveal new therapeutic targets and strategies for the clinical management of NPC. These results establish a rationale for further exploration of MSR1 and ceramides as novel targets in NPC. [ABSTRACT FROM AUTHOR]

Objective：To discuss the expression level of macrophage scavenger receptor 1 (MSR1) in pan-cancer tissue，survival and immune characteristics of the patients by bioinformatics analysis, and to elucidate the value of MSR1 as a new biomarker for the tumor diagnosis, prognosis, and immunotherapy. Methods：Clinical Bioinformatic Database and Sangerbox Database were used to analyze the expression levels of MSR1 mRNA in normal tissue and tumor tissue，the expression of MSR1 protein was analyzed by The Human Protein Atlas (HPA) Database，and univariate survival analysis and Kaplan-Meier analysis were used to evaluate the prognostic value of MSR1，and the expressions of MSR1 in various types of cells were analyzed with single-cell sequencing results from Tumor Immune Single-cell Hub (TISCH) Database；Tumor Immune Estimation Resource (TIMER2. 0)，Tumor Immune Syngeneic Mouse (TISMO), Tumor Immune Dysfunction and Exclusion (TIDE), and Gene Set Cancer Analysis (GSCA) Databases were used to analyze the correlations between the MSR1 expression level in pan-cancer tissue and immune cell infiltration, immune checkpoint gene expression, and immune treatment response. Results：Compared with normal tissue, the expression levels of MSR1 mRNA in 17 kinds of tumor tissues including breast invasive carcinoma (BRCA)，colon adenocarcinoma (COAD)，esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC)，kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP)，brain low-grade glioma (LGG)，liver hepatocellular carcinoma (LIHC)，ovarian serous cystadenocarcinoma (OV)，pancreatic adenocarcinoma (PAAD)，prostate adenocarcinoma (PRAD)，skin cutaneous melanoma (SKCM)，stomach adenocarcinoma (STAD)，testicular germ cell tumor (TGCT)，thyroid carcinoma (THCA), and uterine carcinosarcoma (UCS) were increased (P<0. 01)；compared with normal tissue，the expression levels of MSR1 protein in breast cancer, endometrial cancer, liver cancer, ovarian cancer, skin melanoma, testis cancer, pancreatic cancer, and prostate cancer tissues were increased in varying degrees. The high expressions of MSR1 in bladder urothelial carcinoma ［BLCA, hazard ratio (HR)=1. 01，P=0. 047, 95%CI (1. 00，1. 03)］, LGG ［HR=1. 03，P<0. 001，95%CI (1. 02，1. 04)］, LIHC ［HR=1. 04，P= 0. 007，95%CI (1. 01，1. 07)］, OV ［HR=1. 02，P=0. 028，95%CI (1. 00，1. 03)］, STAD ［HR=1. 02, P=0. 016，95%CI (1. 00，1. 04)］, THCA［HR=1. 06，P=0. 006，95%CI (1. 02，1. 11)］ and uveal melanoma ［UVM, HR=1. 18，P=0. 044，95%CI (1. 00，1. 40)］ were correlated with the poor overall survival (OS) of the patients； the high expression of MSR1 in LGG ［HR=1. 03，P<0. 001，95%CI (1. 02, 1. 04)]，the uterine corpus endometrial carcinoma (UCEC］，［HR=1. 05，P=0. 038，95%CI (1. 00, 1. 10)], and UVM ［HR=1. 2，P=0. 036，95%CI (1. 01，1. 41)］ was correlated with poor disease-specific surival (DSS). The single-cell sequencing results indicated that MSR1 was mainly expressed in the dendritic cell (DC) and monocyte-macrophage. The MSR1 expression was positive correlated with various kinds of immune cell infiltrations (P<0. 05)，including CD8+ T lymphocytes, natural killing (NK) cells, regulatory T lymphocytes, and cancer associated fibroblasts (CAF). There were significant positive correlations between MSR1 and classical immune checkpoint gene and immunotherapy response marker (P<0. 05). Conclusion：MSR1 is highly expressed in lots of tumor tissues and is closely associated with the poor prognosis and immune factors of lots of tumor patients. MSR1 may be a diagnostic tumor marker and a predictor of tumor prognosis and immunotherapy efficacy, and has the potential to be a new therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract Background The therapeutic effects of conventional treatment on gliomas are not promising. The tumor microenvironment (TME) has a close association with the invasiveness of multiple types of tumors, including low‐grade gliomas (LGG). This study aims to validate the prognostic and immune‐related role of macrophage scavenger receptor 1 (MSR1) in LGG patients. Methods Data in this study were obtained from public databases. The differential expression of MSR1 was analyzed in LGG patients with different clinicopathological characteristics. Kaplan–Meier survival analysis, a time‐dependent receiver operating characteristic (ROC) curve, and Cox regression analysis were used to assess the prognostic value of MSR1. Differentially expressed genes (DEGs) were screened between the high and low expression groups of MSR1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to annotate the function of these DEGs. Hallmark gene sets were identified based on MSR1 by Gene Set Enrichment Analysis (GSEA). Difference analysis and correlation analysis were used to study the relationship between MSR1 and TME‐related scores, tumor‐infiltrating immune cells (TIICs), immune‐related gene sets, and immune checkpoints (ICPs). The single‐cell sequencing data were processed to identify the cell types expressing MSR1. The quantification of TIICs in TME was calculated by single‐sample gene set enrichment analysis (ssGSEA). The differential expression of MSR1 in LGG and control brain tissues was verified by experiments. Results There were significant differences in the expression level of MSR1 in different types of tissues and cells. MSR1 has a high prognostic value in LGG patients and can be used as an independent prognostic factor. MSR1 is closely related to TME and may play an important role in the immunotherapy of LGG patients. Conclusions The result of our study demonstrated that MSR1 is an independent prognostic biomarker in LGG patients and may play an important role in the TME of LGGs.

Background: The therapeutic effects of conventional treatment on gliomas are not promising. The tumor microenvironment (TME) has a close association with the invasiveness of multiple types of tumors, including low‐grade gliomas (LGG). This study aims to validate the prognostic and immune‐related role of macrophage scavenger receptor 1 (MSR1) in LGG patients. Methods: Data in this study were obtained from public databases. The differential expression of MSR1 was analyzed in LGG patients with different clinicopathological characteristics. Kaplan–Meier survival analysis, a time‐dependent receiver operating characteristic (ROC) curve, and Cox regression analysis were used to assess the prognostic value of MSR1. Differentially expressed genes (DEGs) were screened between the high and low expression groups of MSR1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to annotate the function of these DEGs. Hallmark gene sets were identified based on MSR1 by Gene Set Enrichment Analysis (GSEA). Difference analysis and correlation analysis were used to study the relationship between MSR1 and TME‐related scores, tumor‐infiltrating immune cells (TIICs), immune‐related gene sets, and immune checkpoints (ICPs). The single‐cell sequencing data were processed to identify the cell types expressing MSR1. The quantification of TIICs in TME was calculated by single‐sample gene set enrichment analysis (ssGSEA). The differential expression of MSR1 in LGG and control brain tissues was verified by experiments. Results: There were significant differences in the expression level of MSR1 in different types of tissues and cells. MSR1 has a high prognostic value in LGG patients and can be used as an independent prognostic factor. MSR1 is closely related to TME and may play an important role in the immunotherapy of LGG patients. Conclusions: The result of our study demonstrated that MSR1 is an independent prognostic biomarker in LGG patients and may play an important role in the TME of LGGs. [ABSTRACT FROM AUTHOR]

The progression of prion diseases is accompanied by the accumulation of prions in the brain. Ablation of microglia enhances prion accumulation and accelerates disease progression, suggesting that microglia play a neuroprotective role by clearing prions. However, the mechanisms underlying the phagocytosis and clearance of prion are largely unknown. The macrophage scavenger receptor 1 (Msr1) is an important phagocytic receptor expressed by microglia in the brain and is involved in the uptake and clearance of soluble amyloid-β. We therefore asked whether Msr1 might play a role in prion clearance and assessed the scavenger function of Msr1 in prion pathogenesis. We found that Msr1 expression was upregulated in prion-infected mouse brains. However, Msr1 deficiency did not change prion disease progression or lesion patterns. Prion deposition in Msr1 deficient mice was similar to their wild-type littermates. In addition, prion-induced neuroinflammation was not affected by Msr1 ablation. We conclude that Msr1 does not play a major role in prion pathogenesis. Key messages: Msr1 expression is upregulated in prion-infected mouse brains at the terminal stage Msr1 deficiency does not affect prion disease progression Msr1 does not play a major role in prion clearance or prion pathogenesis Microglia-mediated phagocytosis and clearance of Aβ and prion may adopt distinct molecular pathways [ABSTRACT FROM AUTHOR]

Sepsis is defined as a life-threatening multiorgan dysfunction caused by dysregulated inflammatory response to infection. It remains the primary cause of death from infection if not diagnosed and treated promptly. Therefore, a better understanding of the mechanism for resolving inflammation is needed. Monocytes and macrophages play a pivotal role not only in the induction but also in the suppression of inflammation. However, a tissue-resident macrophage subset that regulates a hyperinflammatory state during sepsis has not been explored. Here we show that CD204+ monocytes and/or macrophages rescued mice from endotoxin-induced septic shock. Serum and tissue proinflammatory cytokine levels were significantly upregulated in the absence of these cells. This study provided evidence that CD204+ monocytes and/or macrophages ameliorate septic shock by suppressing proinflammatory cytokine production.

Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL‐4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL‐4‐activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL‐4‐activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti‐inflammatory to a pro‐inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo. Altogether, we identified that MSR1 signals through JNK via K63 polyubiquitylation and provides evidence for the receptor's involvement in macrophage polarization. Synopsis: Macrophage scavenger receptor MSR1 is a key phagocytic receptor for the uptake of lipids and cell debris in macrophages. In IL‐4 activated macrophages MSR1 becomes ubiquitylated, recruits the Tak1/MKK7 kinase complex and signals directly through JNK, which induces pro‐inflammatory cytokine production. Proteomics analysis of phagosomes indicate that alternative activation by IL‐4 enhances phagosomal homeostatic functions in macrophages.Triggering of MSR1 in IL‐4 activated macrophages leads to its ubiquitylation, which recruits the TAK1/MKK7/JNK kinase complex.This leads to pro‐inflammatory signalling, inducing a phenotypic switch of the macrophages.MSR1 ubiquitylation and enhanced JNK signalling is present in human tumour associated macrophages. [ABSTRACT FROM AUTHOR]

The DEAD box protein DDX5, an ATP-dependent RNA helicase, plays an important role in transcriptional regulation and is associated with solid tumors and leukemia. However, its role in oxLDL-induced lipid uptake in macrophages remains unclear. In this study, we detected the expression of DDX5 mRNA and protein in oxidized low-density lipoprotein (oxLDL)-treated human primary macrophages that were induced from monocytes isolated from human peripheral blood with or without several chemical inhibitors using quantitative real-time PCR (qRT-PCR) or Western blotting. We found that oxLDL induced DDX5 expression to be independent of both the MAPK and NF-κB pathways. We also found that DDX5 promoted macrophage lipid uptake by evaluating the fluorescence intensity of engulfed dil-oxLDL. Various scavenger receptors that participate in lipid uptake were detected in siR-DDX5 transfected macrophages using qRT-PCR and Western blotting. Macrophage scavenger receptor A (MSR1) was found to be involved the upregulation of DDX5-mediated lipid uptake. Through the use of a dual luciferase reporter assay system and incubation with cycloheximide (CHX) MG132 and actidione (ActD), we found that DDX5 promoted MSR1 protein expression by stabilizing MSR1 mRNA. Moreover, the mechanism involved in DDX5 regulation of MSR1 mRNA was also explored using mass spectrum analysis; Immunoprecipitations (IPs) and RNA- Immunoprecipitations (R-IPs) revealed that mettl3 was involved in DDX5-mediated MSR1 mRNA stabilization. In addition, we also demonstrated that DDX5 inhibited mettl3 to catalyze m 6 a methylation in MSR1 mRNA, which contributed to the maintenance of MSR1 mRNA stability. In conclusion, ox-LDL promotes DDX5 expression in macrophages, which interacts with mettl3 to stabilize MSR1 mRNA by decreasing the m 6 a modification of MSR1 mRNA, ultimately promoting lipid uptake in macrophages. [ABSTRACT FROM AUTHOR]

The present study assessed the association between the variants of macrophage scavenger receptor (MSR)1 and chronic obstructive pulmonary disease (COPD), with or without lung cancer in China. COPD and lung cancer were previously regarded as two separate diseases. However, it has since been reported that there are close associations between COPD and lung cancer. Lung cancer may be an outcome of COPD. COPD may also coexist with lung cancer, and patients with COPD with lung cancer tend to have increased mortality. It is important to have a better understanding of the pathogenesis of COPD and the reason why it develops into lung cancer. MSR1 serves a crucial function in phagocytosis, which may be associated with the pathogenesis of COPD and lung cancer in patients with COPD. From 1 July 2015 to 20 February 2016, 100 patients with COPD and lung cancer, 100 patients with COPD without lung cancer and 100 healthy smokers were enrolled at the Shanghai Ruijin Hospital (Shanghai, China) for the genotyping of eight single-nucleotide polymorphisms (SNPs; ex3P36A_C>G, ex3S41Y_C>A, ex4V113A_T>C, ex4P174Y_ G>T, ex6P275A_C>G, ex6R293x_C>T, ex10G369S_G>A and ex11H441R_A>G) via gene sequencing. The genotype frequencies of these SNPs did not significantly differ between patients with COPD with and without lung cancer, and the healthy controls. However, during DNA sequencing, the SNP rs13306550 (IVS4+3A>G) was identified in the splice donor site and was significantly associated with an increased risk of COPD compared with the healthy smokers (P=0.0053). The present study demonstrated that the variant rs13306550 was a risk factor for COPD susceptibility, but that did not influence lung cancer pathogenesis in patients with COPD. However, the mechanisms underlying the influence of rs13306550 on COPD development and progression remain to be elucidated and require further study. [ABSTRACT FROM AUTHOR]

Background & Aims The macrophage scavenger receptor 1 (Msr1, also called SRA) is a pattern recognition receptor primarily expressed on myeloid cells, which plays an important role in the maintenance of immune homeostasis. Since MSR1 expression was upregulated in the livers of patients with fulminant hepatitis (FH), we investigated the functional mechanism of Msr1 in FH pathogenesis. Methods Msr1 -deficient ( Msr1 −/− ) mice and their wild-type (WT) littermates were infected with mouse hepatitis virus strain-A59 (MHV-A59) to induce FH, and the levels of tissue damage, serum alanine aminotransferase, inflammatory cytokines and complement component 5a (C5a) were measured and compared. Liver injury was studied after MHV infection with or without neutrophil depletion. Results Our results showed that Msr1 −/− mice were resistant to MHV-induced hepatitis. Treatment with the C5a receptor antagonist (C5aRa) diminished the differences in inflammatory responses and liver injury between MHV-infected wild-type and Msr1 −/− mice, suggesting that C5a-induced pro-inflammatory response plays a critical role in the Msr1-mediated regulation of FH pathogenesis. We demonstrated that Msr1 efficiently enhanced transforming growth factor-activated kinase-1 phosphorylation in neutrophils upon MHV-A59 stimulation, thereby promoting the activation of the extracellular signal-regulated kinase pathway and subsequent NETosis formation. Moreover, we provided evidence that blockage of Msr1 attenuated the liver damage caused by MHV-A59 infection. Conclusions Msr1 promotes the pathogenesis of virus-induced FH by enhancing induction of neutrophil NETosis and subsequent complement activation. Targeting Msr1 may be employed as a new immunotherapeutic strategy for FH. Lay summary Virus-induced fulminant hepatitis (FH) is a disease with a high mortality worldwide. Enhanced levels of macrophage scavenger receptor 1 (Msr1) in the liver of patients with FH and of murine experimental FH indicated Msr1 plays a role in the pathogenesis of FH. Herein, we demonstrate that mice deficient in Msr1 are resistant to FH induced by MHV-A59, and the Msr1 inhibitor fucoidan suppresses the progression of FH in mice. Our study suggests that use of drugs inhibiting MSR1 function could be beneficial to patients with FH. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extracranial solid tumour in children and is histologically classified by its Schwannian stromal cells. Although having fewer Schwannian stromal cells is generally associated with more aggressive phenotypes, the exact roles of other stromal cells (mainly macrophages and fibroblasts) are unclear. Here, we examined 41 cases of neuroblastoma using immunohistochemistry for the tumour-associated macrophage (TAM) markers CD68, CD163, and CD204, and a cancer-associated fibroblast (CAF) marker, alpha smooth muscle actin (?SMA). Each case was assigned to low/high groups on the basis of the number of TAMs or three groups on the basis of the ?SMA-staining area for CAFs. Both the number of TAMs and the area of CAFs were significantly correlated with clinical stage, MYCN amplification, bone marrow metastasis, histological classification, histological type, and risk classification. Furthermore, TAM settled in the vicinity of the CAF area, suggesting their close interaction within the tumour microenvironment. We next determined the effects of conditioned medium of a neuroblastoma cell line (NBCM) on bone marrow-derived mesenchymal stem cells (BM-MSCs) and peripheral blood mononuclear cell (PBMC)-derived macrophages in vitro. The TAM markers CD163 and CD204 were significantly up-regulated in PBMC-derived macrophages treated with NBCM. The expression of ?SMA by BM-MSCs was increased in NBCM-treated cells. Co-culturing with CAF-like BM-MSCs did not enhance the invasive ability but supported the proliferation of tumour cells, whereas tumour cells co-cultured with TAM-like macrophages had the opposite effect. Intriguingly, TAM-like macrophages enhanced not only the invasive abilities of tumour cells and BM-MSCs but also the proliferation of BM-MSCs. CXCL2 secreted from TAM-like macrophages plays an important role in tumour invasiveness. Taken together, these results indicate that PBMC-derived macrophages and BM-MSCs are recruited to a tumour site and activated into TAMs and CAFs, respectively, followed by the formation of favourable environments for neuroblastoma progression. [ABSTRACT FROM AUTHOR]

Macrophages are distributed in all peripheral tissues and play a critical role in the first line of the innate immune defenses against bacterial infection by phagocytosis of bacterial pathogens through the macrophage scavenger receptor 1 (MSR1). Within tissues, the partial pressure of oxygen ( pO2) decreases depending on the distance of cells from the closest O2-supplying blood vessel. However, it is not clear how the expression of MSR1 in macrophages is regulated by low pO2. On the other hand, hypoxia-inducible factor (HIF)-1α is well known to control hypoxic responses through regulation of hypoxia-inducible genes. Therefore, we investigated the effects of hypoxia and HIF-1α on MSR1 expression and function in the macrophage cell line RAW264. Exposure to 1% O2 or treatment with the hypoxia-mimetic agent cobalt chloride (CoCl2) significantly suppressed the expression of MSR1 mRNA, accompanied by a markedly increase in levels of nuclear HIF-1α protein. The overexpression of HIF-1α in RAW264 cells suppressed the expression of MSR1 mRNA and protein, transcriptional activity of the MSR1 gene, and phagocytic capacity against the Gram-positive bacteria Listeria monocytogenes. The suppression of MSR1 mRNA by hypoxia or CoCl2 was inhibited by YC-1, an inhibitor of HIF-1α, or by the depletion of HIF-1α expression by small interference RNA. These results indicate that hypoxia transcriptionally suppresses MSR1 expression through HIF-1α. [ABSTRACT FROM AUTHOR]

Microglial activation followed by recruitment of blood-borne macrophages into the central nervous system (CNS) aggravates neuroinflammation. Specifically, in multiple sclerosis (MS) as well as in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, activated microglia and macrophages (Mg/Mφ) promote proinflammatory responses and expand demyelination in the CNS. However, a potent therapeutic approach through the systemic route for regulating their functions has not yet been developed. Here, we demonstrate that a systemically injected DNA/RNA heteroduplex oligonucleotide (HDO), composed of an antisense oligonucleotide (ASO) and its complementary RNA, conjugated to cholesterol (Chol-HDO) distributed more efficiently to demyelinating lesions of the spinal cord in EAE mice with significant gene silencing than the parent ASO. Importantly, systemic administration of Cd40-targeting Chol-HDO improved clinical signs of EAE with significant downregulation of Cd40 in Mg/Mφ. Furthermore, we successfully identify that macrophage scavenger receptor 1 (MSR1) is responsible for the uptake of Chol-HDO by Mg/Mφ of EAE mice. Overall, our findings demonstrate the therapeutic potency of systemically administered Chol-HDO to regulate activated Mg/Mφ in neuroinflammation., Competing Interests: Declaration of interests T.Y. collaborates with Daiichi Sankyo Co., Ltd., Rena Therapeutics Inc., and Takeda Pharmaceutical Co., Ltd., and serves as an academic advisor for Rena Therapeutics Inc. The other authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in regulating bone marrow stem cell (BMSC) differentiation through the osteogenic pathway during fracture healing has attracted much attention. Methods : The tibial monocortical defect model was employed to determine the critical role of macrophage scavenger receptor 1 (MSR1) during intramembranous ossification (IO) in vivo . The potential functions and mechanisms of MSR1 were explored in a co-culture system of bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and BMSCs using qPCR, Western blotting, immunofluorescence, and RNA sequencing. Results : In this study, using the tibial monocortical defect model, we observed delayed IO in MSR1 knockout (KO) mice compared to MSR1 wild-type (WT) mice. Furthermore, macrophage MSR1 mediated PI3K/AKT/GSK3β/β-catenin signaling increased ability to promote osteogenic differentiation of BMSCs in the co-culture system. We also identified proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) as the target gene for macrophage MSR1-activated PI3K/AKT/GSK3β/β-catenin pathway in the co-culture system that facilitated M2-like polarization by enhancing mitochondrial oxidative phosphorylation. Conclusion : Our findings revealed a previously unrecognized function of MSR1 in macrophages during fracture repair. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)