Macrophage Subsets Research Articles

Distinct hypoxia-induced translational profiles of embryonic and adult-derived macrophages

Tissue resident macrophages are largely of embryonic (fetal liver) origin and long-lived, while bone marrow-derived macrophages (BMDM) are recruited following an acute perturbation, such as hypoxia in the setting of myocardial ischemia. Prior transcriptome analyses identified BMDM and fetal liver-derived macrophage (FLDM) differences at the RNA expression level. Posttranscriptional regulation determining mRNA stability and translation rate may override transcriptional signals in response to hypoxia. We profiled differentially regulated BMDM and FLDM transcripts in response to hypoxia at the level of mRNA translation. Using a translating ribosome affinity purification (TRAP) assay and RNA-seq, we identified non-overlapping transcripts with increased translation rate in BMDM (Ly6e, vimentin, PF4) and FLDM (Ccl7, Ccl2) after hypoxia. We further identified hypoxia-induced transcripts within these subsets that are regulated by the RNA-binding protein HuR. These findings define translational differences in macrophage subset gene expression programs, highlighting potential therapeutic targets in ischemic myocardium.

Crystalline Silica-Induced Proinflammatory Interstitial Macrophage Recruitment through Notch3 Signaling Promotes the Pathogenesis of Silicosis.

Crystalline silica (CS) particles are ubiquitous in the environment, especially in occupational conditions, and exposure to respirable CS causes silicosis. The initial response to CS is mediated by innate immunity, where pulmonary macrophages act as central orchestrators. However, the repercussions of CS on functionally distinct macrophage subsets remain to be inconclusive. Herein, to study the effects of inhaled CS, we divided macrophages into three subsets: circulating monocytes, interstitial macrophages (IMs), and alveolar macrophages (AMs). CS-induced massive IMs increase in the lung, the phenotype and function of which differed from those of tissue-resident AMs and circulating monocytes. The augmented IMs were driven by recruitment of circulating macrophages rather than cell proliferation in situ. Moreover, the IMs predominantly exerted a classic activated (M1) phenotype and expressed proinflammatory cytokines, contributing to CS-induced lung injury. Notably, we demonstrated that IMs augmented Notch3 expression. Mechanistically, using myeloid-specific Notch3-knockout mice, we demonstrated that Notch3 signaling not only promoted IMs recruitment by regulating CCR2 expression but also manipulated the proinflammatory phenotype. Mice with conditional Notch3-knockout exhibited alleviation of CS-induced inflammation and fibrosis in lung. Overall, our study identifies IMs as critical mediators in response to CS and highlights the role of Notch3 in IMs recruitment and activation, providing new insights into CS toxicological effects in the lung.

The Characteristics of Macrophage Heterogeneity in Atherosclerotic Aortas.

Macrophage is the main effector cell during atherosclerosis. We applied single-cell RNA sequencing (scRNA) data to investigate the role of macrophage subsets in atherosclerosis. Monocyte and macrophage clusters were divided into 6 subclusters. Each subcluster's markers were calculated and validated by immunofluorescence. Elevated macrophage subclusters in the WD group were subject to enrichment pathway analysis and exhibited different phenotypes. Pseudotime analysis shows the subclusters originate from monocytes. We cultured bone marrow-derived macrophages with CSF-1 and ox-LDL to simulate an atherosclerotic-like environment and detected the transformation of subclusters. Macrophage-Vegfa and Macrophage-C1qb increased in the WD group. Macrophage-Vegfa acquires the characteristics of phagocytosis and immune response, while Macrophage-C1qb is not involved in lipid metabolism. The two subclusters are both enriched in cell movement and migration pathways. Experimental verification proved Monocyte-Ly6C evolved into Macrophage-Vegfa and Macrophage-C1qb during atherosclerosis progression.

Knowledge Mapping of Macrophage in Spinal Cord Injury: A Bibliometric Analysis

Spinal cord injury (SCI) is a devastating condition, often leading to significant disability and impairment. As crucial immune cells, macrophages play a critical role in the pathophysiology of SCI. Understanding the current state of knowledge and research trends related to macrophages in SCI is crucial for developing effective therapeutic interventions. Using search strategies, we retrieved relevant articles from the Web of Science Core Collection (WOSCC), resulting in a robust dataset for analysis. VOSviewer, Citespace, and PRISM were employed for analysis and visualization. Various bibliometric indicators, including publication trends, citation analysis, co-authorship networks, and keyword analysis, were utilized to assess the scholarly landscape of macrophage research in SCI. Our findings revealed a steady increase in publications over the past 33years, indicating a growing interest in this field. We identified Popovich Phillip G was the most influential author, Ohio State University was the most influential institution, and identification of 2 distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord was the most influential paper in this field. This bibliometric analysis provides a comprehensive overview of the current knowledge landscape and research trends regarding macrophages in SCI. Neuroinflammation and macrophage polarization, transplation and molecular mechanism were emerging research areas and novel directions. Our study serves as a valuable resource for researchers in spinal cord injury research and therapeutic development.

Zymosan A Improved Doxorubicin-Induced Ventricular Remodeling by Evoking Heightened Cardiac Inflammatory Responses and Healing in Mice.

Background Doxorubicin-induced myocardial injury is reflected by the presence of vacuolization in both clinical and animal models. The lack of scar tissue to replace the vacuolizated cardiomyocytes indicates that insufficient cardiac inflammation and healing occurred following doxorubicin injection. Whether improved macrophage activity by zymosan A (zymosan) ameliorates doxorubicin-induced ventricular remodeling in mice is unknown. Methods and Results Mice were intravenously injected with vehicle or doxorubicin (5 mg/kg per week, 4 weeks), and cardiac structure and function were assessed by echocardiography. Two distinct macrophage subsets in hearts following doxorubicin injection were measured at different time points by flow cytometry. Moreover, cardiomyocyte vacuolization, capillary density, collagen content, and ventricular tensile strength were assessed. The therapeutic effect of zymosan (3 mg/kg, single injection) on doxorubicin-induced changes in the aforementioned parameters was determined. At the cellular level, the polarization of monocytes to proinflammatory or reparative macrophages were measured, with or without doxorubicin (0.25 and 0.5 μmol/L). Doxorubicin led to less proinflammatory and reparative macrophage infiltration in the heart in the early phase, with decreased cardiac capillary density and collagen III in the chronic phase. In cell culture, doxorubicin (0.5 μmol/L) repressed macrophage transition toward both proinflammatory and reparative subset. Zymosan enhanced both proinflammatory and reparative macrophage infiltration in doxorubicin-injected hearts, evoking a heightened acute inflammatory response. Zymosan alleviated doxorubicin-induced cardiomyocyte vacuolization in the chronic phase, in parallel with enhanced collagen content, capillary density, and ventricular tensile strength. Conclusions Zymosan improved cardiac healing and ameliorated doxorubicin-induced ventricular remodeling and dysfunction by activating macrophages at an optimal time.

The multifaceted role of macrophages during acute liver injury.

The liver is situated at the interface of the gut and circulation where it acts as a filter for blood-borne and gut-derived microbes and biological molecules, promoting tolerance of non-invasive antigens while driving immune responses against pathogenic ones. Liver resident immune cells such as Kupffer cells (KCs), a subset of macrophages, maintain homeostasis under physiological conditions. However, upon liver injury, these cells and others recruited from circulation participate in the response to injury and the repair of tissue damage. Such response is thus spatially and temporally regulated and implicates interconnected cells of immune and non-immune nature. This review will describe the hepatic immune environment during acute liver injury and the subsequent wound healing process. In its early stages, the wound healing immune response involves a necroinflammatory process characterized by partial depletion of resident KCs and lymphocytes and a significant infiltration of myeloid cells including monocyte-derived macrophages (MoMFs) complemented by a wave of pro-inflammatory mediators. The subsequent repair stage includes restoring KCs, initiating angiogenesis, renewing extracellular matrix and enhancing proliferation/activation of resident parenchymal and mesenchymal cells. This review will focus on the multifaceted role of hepatic macrophages, including KCs and MoMFs, and their spatial distribution and roles during acute liver injury.

Curcumin mediates macrophage polarization to inhibit the formation of abdominal aortic aneurysms by inhibiting the expression of histone acetyltransferase EP300

BackgroundThe onset of abdominal aortic aneurysm (AAA) is caused by local dilatation of the infrarenal abdominal aorta. Curcumin can affect the polarization and function of macrophage subsets in the context of vascular diseases. Curcumin, a natural EP300 inhibitor, may have therapeutic effects on vascular diseases. ObjectiveTo explore the therapeutic pathway of curcumin in AAA. MethodsWe found that the hub regulatory factor EP300 is the key factor by which curcumin acts on AAA through bioinformatics network pharmacology and molecular docking. We verified the localization of histone acetyltransferase EP300 in AAA tissue by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, we used Real-time polymerase chain reaction (RT-PCR) to explore the high expression level of EP300 in human AAA tissues and analysed its correlation with key genes in AAA diseases. In addition, we successfully induced M1 macrophages and EP300 knockout macrophages with LPS/IFN-γ in vitro to investigate the effect of EP300 on macrophage polarization. ResultsIn our study, thirty important targets, including AKT1, STAT3, EGFR, EP300, GSK3B, APP, SERPINE1 and MMP14, were involved in the interaction between AAA and curcumin. Our molecular docking results showed that EP300 spontaneously binds to curcumin most easily. Therefore, we subsequently identified the histone acetyltransferase EP300 as the hub target of curcumin in AAA. IHC and IF staining of the outer membrane of AAA showed that EP300 was located in the mesa of AAA tissue, which was also the place where macrophages gathered. The mRNA expression of EP300 in human AAA tissue was upregulated, as shown by RT-PCR (P = 0.01). In in vitro RAW264.7 cells, we found that EP300 knockout in M0 macrophages significantly promoted the anti-inflammatory M2 polarization of macrophages and inhibited the proinflammatory M1 polarization of macrophages. ConclusionOur research showed that in the therapeutic mechanism by which curcumin treats human AAA, histone acetyltransferase EP300 affected the progression of AAA by promoting aortic inflammation, acting on the immune environment, modulating macrophage proinflammatory polarization, and influencing the expression of other AAA target genes.

Macrophage and monocyte subsets in response to ischemic stroke.

Ischemic stroke is a leading cause of disability and mortality. Despite extensive efforts in stroke research, the only pharmacological treatment currently available is arterial recanalization, which has limited efficacy only in the acute phase of stroke. The neuroinflammatory response to stroke is believed to provide a wider time window than recanalization and has therefore been proposed as an attractive therapeutic target. In this review, we provide an overview of recent advances in the understanding of cellular and molecular responses of distinct macrophage populations following stroke, which may offer potential targets for therapeutic interventions. Specifically, we discuss the role of local responders in neuroinflammation, including the well-studied microglia as well as the emerging players, border-associated macrophages, and macrophages originating from the skull bone marrow. Additionally, we focus on the behavior of monocytes stemming from distant tissues, such as the bone marrow and spleen. Finally, we highlight aging as a crucial factor modulating the immune response, which is often neglected in animal studies. This article is protected by copyright. All rights reserved.

TREM1 activation of myeloid cells promotes antitumor immunity.

Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses. TREM1 is expressed on neutrophils, subsets of monocytes and tissue macrophages, and suppressive myeloid populations in the TME, including tumor-associated neutrophils, monocytes, and tumor-associated macrophages. Depletion or inhibition of immunosuppressive myeloid cells, or stimulation by TREM1-mediated inflammatory signaling, could be used to promote an immunostimulatory TME. We developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody with enhanced FcγR binding. PY159 is a TREM1 agonist that induces signaling, leading to up-regulation of costimulatory molecules on monocytes and macrophages, production of proinflammatory cytokines and chemokines, and enhancement of T cell activation in vitro. An antibody against mouse TREM1, PY159m, promoted antitumor efficacy in syngeneic mouse tumor models. These results suggest that PY159-mediated agonism of TREM1 on tumoral myeloid cells can promote a proinflammatory TME and offer a promising strategy for immunotherapy.

Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis.

Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However, it remains unclear whether trained immunity of tissue-resident macrophages also enhances injury resolution to counterbalance the heightened inflammatory responses. Here, we studied lung-resident alveolar macrophages (AMs) prechallenged with either the bacterial endotoxin or with Pseudomonas aeruginosa and observed that these trained AMs showed greater resilience to pathogen-induced cell death. Transcriptomic analysis and functional assays showed greater capacity of trained AMs for efferocytosis of cellular debris and injury resolution. Single-cell high-dimensional mass cytometry analysis and lineage tracing demonstrated that training induces an expansion of a MERTKhiMarcohiCD163+F4/80low lung-resident AM subset with a proresolving phenotype. Reprogrammed AMs upregulated expression of the efferocytosis receptor MERTK mediated by the transcription factor KLF4. Adoptive transfer of these trained AMs restricted inflammatory lung injury in recipient mice exposed to lethal P. aeruginosa. Thus, our study has identified a subset of tissue-resident trained macrophages that prevent hyperinflammation and restore tissue homeostasis following repeated pathogen challenges.

Intravenous BCG vaccination reduces SARS-CoV-2 severity and promotes extensive reprogramming of lung immune cells

Bacillus Calmette-Guérin (BCG) confers heterologous immune protection against viral infections and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here, we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model. BCG vaccination conferred a modest reduction on lung SCV2 viral load, bronchopneumonia scores, and weight loss, accompanied by a reversal of SCV2-mediated Tcell lymphopenia, and reduced lung granulocytes. BCG uniquely recruited immunoglobulin-producing plasma cells to the lung suggesting accelerated local antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, with a transcriptional shift away from exhaustion markers and toward antigen presentation and repair. Similarly, BCG enhanced recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, that show reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

The maintenance mechanism of hematopoietic stem cell dormancy: role for a subset of macrophages

The maintenance mechanism of hematopoietic stem cell dormancy: role for a subset of macrophages

Integration of single-cell RNA sequencing and bulk RNA transcriptome sequencing reveals a heterogeneous immune landscape and pivotal cell subpopulations associated with colorectal cancer prognosis.

Colorectal cancer (CRC) is a highly heterogeneous cancer. The molecular and cellular characteristics differ between the colon and rectal cancer type due to the differences in their anatomical location and pathological properties. With the advent of single-cell sequencing, it has become possible to analyze inter- and intra-tumoral tissue heterogeneities. A comprehensive CRC immune atlas, comprising 62,398 immune cells, was re-structured into 33 immune cell clusters at the single-cell level. Further, the immune cell lineage heterogeneity of colon, rectal, and paracancerous tissues was explored. Simultaneously, we characterized the TAM phenotypes and analyzed the transcriptomic factor regulatory network of each macrophage subset using SCENIC. In addition, monocle2 was used to elucidate the B cell developmental trajectory. The crosstalk between immune cells was explored using CellChat and the patterns of incoming and outgoing signals within the overall immune cell population were identified. Afterwards, the bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) were combined and the relative infiltration abundance of the identified subpopulations was analyzed using CIBERSORT. Moreover, cell composition patterns could be classified into five tumor microenvironment (TME) subtypes by employing a consistent non-negative matrix algorithm. Finally, the co-expression and interaction between SPP1+TAMs and Treg cells in the tumor microenvironment were analyzed by multiplex immunohistochemistry. In the T cell lineage, we found that CXCL13+T cells were more widely distributed in colorectal cancer tissues, and the proportion of infiltration was increased. In addition, Th17 was found accounted for the highest proportion in CD39+CD101+PD1+T cells. Mover, Ma1-SPP1 showed the characteristics of M2 phenotypes and displayed an increased proportion in tumor tissues, which may promote angiogenesis. Plasma cells (PCs) displayed a significantly heterogeneous distribution in tumor as well as normal tissues. Specifically, the IgA+ PC population could be shown to be decreased in colorectal tumor tissues whereas the IgG+ PC one was enriched. In addition, information flow mediated by SPP1 and CD44, regulate signaling pathways of tumor progression. Among the five TME subtypes, the TME-1 subtype displayed a markedly reduced proportion of T-cell infiltration with the highest proportion of macrophages which was correlated to the worst prognosis. Finally, the co-expression and interaction between SPP1+TAMs and Treg cells were observed in the CD44 enriched region. The heterogeneity distribution and phenotype of immune cells were analyzed in colon cancer and rectal cancer at the single-cell level. Further, the prognostic role of major tumor-infiltrating lymphocytes and TME subtypes in CRC was evaluated by integrating bulk RNA. These findings provide novel insight into the immunotherapy of CRC.

Abstract IA019: Metabolic adaptations in renal cell carcinoma

Abstract Clear cell renal cell carcinoma (ccRCC) is characterized by deregulated hypoxic signaling, metabolic defects, and a complex tumor microenvironment (TME) highly enriched in both lymphoid and myeloid immune subsets. Loss of the oxygen sensing gene, von Hippel Lindau (VHL), is a critical early event in ccRCC pathogenesis and promotes stabilization of hypoxia inducible (transcription) factors (HIF) that upregulate pro-growth signaling pathways, including angiogenesis and aerobic glycolysis. However, whether Vhl loss in cancer cells impacts the frequency, energetic requirements, or other functional properties of immune subsets in the TME remains unclear. Here, using Vhl WT and Vhl KO in vivo murine kidney cancer models, we found that Vhl KO tumors across multiple clones were slower growing and promoted increased immune cell infiltration in the TME. Enhanced proinflammatory signatures in tumor associated macrophage (TAM) subsets from Vhl deficient tumors were also observed, and these features were rescued when Vhl was reintroduced to the cancer cells. Moreover, in vivo quantification of the PET tracer and glucose analog, [18F]fluorodeoxyglucose (FDG), revealed that both myeloid derived suppressor cells (MDSC) and TAM populations from Vhl KO tumors consume more glucose than myeloid subsets from Vhl intact tumors. Notably, Vhl loss did not confer increased glucose uptake in cancer cells or lymphoid subsets in vivo. Overall, these data are consistent with enhanced metabolism and proinflammatory properties observed in the myeloid compartment of human ccRCC and highlight cancer cell intrinsic mechanisms driving environmental reprograming as a means of shaping the immune landscape in ccRCC. Citation Format: W. Kimryn Rathmell. Metabolic adaptations in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA019.

Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n= 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocyte/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis, we demonstrate that recruitment of MdMs precedes Kupffer cell loss and liver damage. Electron microscopy of isolated macrophages revealed increased lipid accumulation in MdMs, and exvivo lipid transfer experiments suggested that MdMs may serve a distinct role in lipid uptake during MAFLD. The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD.

Abstract P3089: Selective Activation Of Cardiac Macrophages To Study Injury And Repair

Objective: Pathophysiological inflammatory responses play an important role during ischemia-mediated heart injury and remodeling, where monocytes and macrophages appear to be critically involved. Cardiac macrophages are generally classified as a recruited, monocyte-derived subset that is Ccr2 + and a tissue resident subset that is typically Ccr2 - . Recent studies have shown that these two subsets have divergent functions with Ccr2 - macrophages being pro-regenerative while Ccr2 + macrophages are pro-inflammatory. Here we selectively manipulated the content and/or activation of these two macrophage subsets in the heart. Methods and Results: To study the function of Ccr2 + cardiac macrophages in the heart, we have overexpressed Ccl-2 (Mcp-1) ligand specifically in cardiomyocytes by using adeno-associated virus serotype-9 (AAV9) mediated gene transfer. Postnatal day 4 (p4) Ccr2 RFP/+ pups were injected with either AAV9-Ccl-2 or AAV9-control. At two months of age, we observed increased Ccl-2 transcripts and protein expression in the heart as measured by qRT-PCR and ELISA, respectively. By quantifying immune cells using flow cytometry, we observed increased infiltration of Ccr2 + macrophages (CD45 + CD11b + CD64 + ) in the hearts of AAV9-Ccl2 injected mice compared to controls. However, echocardiography analysis revealed no change in cardiac function in adult Ccl-2 overexpressed mice. Moreover, the recruitment of Ccr2 + macrophages into the myocardium did not cause fibroblast expansion or activation. Conclusion: Our results show that cardiomyocyte-specific overexpression of Ccl-2 induces profound infiltration of Ccr2 + macrophages into the myocardium but this did not alter cardiac function or cause fibrosis at two or six months of age.

A comprehensive analysis of the potential role of necroptosis in hepatocellular carcinoma using single-cell RNA Seq and bulk RNA Seq.

Necroptosis plays an essential role in oncogenesis and tumor progression in hepatocellular carcinoma (HCC). This study aimed to investigate the role of necroptosis in the development and progression of HCC. Specifically, we constructed a prognostic prediction model using necroptosis-associated genes (NAGs) to predict patient outcomes. Using data from The Cancer Genome Atlas (TCGA) database, we analyzed gene expression and clinical data. We identified a 5-gene model associated with NAGs and explored genetic features and immune cell infiltration using the CIBERSORT algorithm. In addition, we conducted single-cell RNA sequencing to investigate the potential role of necroptosis in HCC. We constructed a 5-gene prognostic model based on NAGs that demonstrated excellent predictive accuracy in both training and validation sets. Using multifactorial cox regression analysis, we confirmed the risk score derived from the model as an independent predictor of prognosis, surpassing other clinical characteristics. Patients with high risk scores had significantly worse prognosis than those with low risk scores. To enhance the clinical utility of the necroptosis score, we constructed an accurate nomogram. Additionally, we compared metabolic pathway and immune microenvironment differences between HCC tumors with high and low risk scores. Our single-cell RNA sequencing analyses revealed that necroptosis in HCC was primarily associated with a specific subset of macrophages. Our study revealed the presence of two distinct necroptosis subtypes in HCC and developed a robust prognostic model with exceptional predictive accuracy. We observed significantly higher infiltration of M0 macrophages in the high-risk group. We propose that rescuing cytochrome c metabolism in HCC could serve as a potential therapeutic strategy. Furthermore, at a single-cell resolution, our analysis identified myeloid cells as the primary cells exhibiting necroptosis. Specifically, macrophages expressing CD5L, CETP, and MARCO, which may belong to a subset of tissue-resident macrophages, were found to be highly susceptible to necroptosis. These findings suggest the involvement of this specific macrophage subset in potential antitumor therapies. Our study provides novel insights into predicting patient prognosis and developing personalized therapeutic approaches for HCC.

Reanalysis of single-cell data reveals macrophage subsets associated with the immunotherapy response and prognosis of patients with endometrial cancer

Endometrial cancer (EC) is an aggressive gynecological malignancy with an increased incidence rate. The immune landscape crucially affects immunotherapy efficacy and prognosis in EC patients. Here, we characterized the distinct tumor microenvironment signatures of EC tumors by analyzing single-cell RNA sequencing data from Gene Expression Omnibus and bulk RNA sequencing data from The Cancer Genome Atlas, which were compared with normal endometrium. Three macrophage subsets were identified, and two of them showed tissue-specific distribution. One of the macrophage subsets was dominant in macrophages derived from EC and exhibited characteristic behaviors such as promoting tumor growth and metastasis. One of the other macrophage subsets was mainly found in normal endometrium and served functions related to antigen presentation. We also identified a macrophage subset that was found in both EC and normal endometrial tissue. However, the pathway and cellular cross-talk of this subset were completely different based on the respective origin, suggesting a tumor-related differentiation mechanism of macrophages. Additionally, the tumor-enriched macrophage subset was found to predict immunotherapy responses in EC. Notably, we selected six genes from macrophage subset markers that could predict the survival of EC patients, SCL8A1, TXN, ANXA5, CST3, CD74 and NANS, and constructed a prognostic signature. To verify the signature, we identified immunohistochemistry for the tumor samples of 83 EC patients based on the selected genes and further followed up with the survival of the patients. Our results provide strong evidence that the signature can effectively predict the prognosis of EC patients.

The interaction of macrophages and CD8 T cells in bronchoalveolar lavage fluid is associated with latent tuberculosis infection

ABSTRACT Mycobacterium tuberculosis (Mtb) infection, including active tuberculosis (TB) and latent Mtb infection (LTBI), leads to diverse outcomes owing to different host immune responses. However, the immune mechanisms that govern the progression from LTBI to TB remain poorly defined in humans. Here, we profiled the lung immune cell populations within the bronchoalveolar lavage fluid (BALF) from patients with LTBI or TB using single-cell RNA sequencing (scRNA-seq). We found that Mtb infection substantially changed the immune cell compartments in the BALF, especially for the three subsets of macrophages, monocyte macrophage (MM)-CCL23, MM-FCN1, and MM-SPP1, which were found to be associated with the disease status of TB infection. Notably, MM-CCL23 cells derived from monocytes after stimulation with Mtb were characterized by high levels of chemokine (CCL23 and CXCL5) production and might serve as a marker for Mtb infection. The MM-CCL23 population mainly recruited CD8-CCR6 T cells through CCL20/CCR6, which was a prominent feature associated with protection immunity in LTBI. This study improves our understanding of the lung immune landscape during Mtb infection, which may inform future vaccine design for protective immunity.

HMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC

BackgroundUnderstanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the...