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Proceedings of the National Academy of... Apr 2023Multiple sclerosis (MS) is an incurable autoimmune disease and is currently treated by systemic immunosuppressants with off-target side effects. Although aberrant...
Multiple sclerosis (MS) is an incurable autoimmune disease and is currently treated by systemic immunosuppressants with off-target side effects. Although aberrant myeloid function is often observed in MS plaques in the central nervous system (CNS), the role of myeloid cells in therapeutic intervention is currently overlooked. Here, we developed a myeloid cell-based strategy to reduce the disease burden in experimental autoimmune encephalomyelitis (EAE), a mouse model of progressive MS. We developed monocyte-adhered microparticles ("backpacks") for activating myeloid cell phenotype to an anti-inflammatory state through localized interleukin-4 and dexamethasone signals. We demonstrate that backpack-laden monocytes infiltrated into the inflamed CNS and modulated both the local and systemic immune responses. Within the CNS, backpack-carrying monocytes regulated both the infiltrating and tissue-resident myeloid cell compartments in the spinal cord for functions related to antigen presentation and reactive species production. Treatment with backpack-monocytes also decreased the level of systemic pro-inflammatory cytokines. Additionally, backpack-laden monocytes induced modulatory effects on T1 and T17 populations in the spinal cord and blood, demonstrating cross talk between the myeloid and lymphoid arms of disease. Backpack-carrying monocytes conferred therapeutic benefit in EAE mice, as quantified by improved motor function. The use of backpack-laden monocytes offers an antigen-free, biomaterial-based approach to precisely tune cell phenotype in vivo, demonstrating the utility of myeloid cells as a therapeutic modality and target.
Topics: Mice; Animals; Multiple Sclerosis; Myeloid Cells; Encephalomyelitis, Autoimmune, Experimental; Central Nervous System; Monocytes; Mice, Inbred C57BL
PubMed: 37075071
DOI: 10.1073/pnas.2221535120 -
Clinical Science (London, England :... Oct 2023Myeloid cells, including macrophages, play important roles as first responders to cardiac injury and stress. Epidermal growth factor receptor (EGFR) has been identified...
Myeloid cells, including macrophages, play important roles as first responders to cardiac injury and stress. Epidermal growth factor receptor (EGFR) has been identified as a mediator of macrophage responsiveness to select diseases, though its impact on cardiac function or remodeling following acute ischemic injury is unknown. We aimed to define the role of myeloid cell-specific EGFR in the regulation of cardiac function and remodeling following acute myocardial infarction (MI)-induced injury. Floxed EGFR mice were bred with homozygous LysM-Cre (LMC) transgenic mice to yield myeloid-specific EGFR knockout (mKO) mice. Via echocardiography, immunohistochemistry, RNA sequencing and flow cytometry, the impact of myeloid cell-specific EGFR deletion on cardiac structure and function was assessed at baseline and following injury. Compared with LMC controls, myeloid cell-specific EGFR deletion led to an increase in cardiomyocyte hypertrophy at baseline. Bulk RNASeq analysis of isolated cardiac Cd11b+ myeloid cells revealed substantial changes in mKO cell transcripts at baseline, particularly in relation to predicted decreases in neovascularization. In response to myocardial infarction, mKO mice experienced a hastened decline in cardiac function with isolated cardiac Cd11b+ myeloid cells expressing decreased levels of the pro-reparative mediators Vegfa and Il10, which coincided with enhanced cardiac hypertrophy and decreased capillary density. Overall, loss of EGFR qualitatively alters cardiac resident macrophages that promotes a low level of basal stress and a more rapid decrease in cardiac function along with worsened repair following acute ischemic injury.
Topics: Mice; Animals; ErbB Receptors; Myeloid Cells; Macrophages; Heart; Myocardial Infarction; Mice, Transgenic; Mice, Knockout; Mice, Inbred C57BL; Ventricular Remodeling
PubMed: 37728308
DOI: 10.1042/CS20230804 -
Immunity Jul 2021Myeloid cells encounter stromal cells and their matrix determinants on a continual basis during their residence in any given organ. Here, we examined the impact of the...
Myeloid cells encounter stromal cells and their matrix determinants on a continual basis during their residence in any given organ. Here, we examined the impact of the collagen receptor LAIR1 on myeloid cell homeostasis and function. LAIR1 was highly expressed in the myeloid lineage and enriched in non-classical monocytes. Proteomic definition of the LAIR1 interactome identified stromal factor Colec12 as a high-affinity LAIR1 ligand. Proteomic profiling of LAIR1 signaling triggered by Collagen1 and Colec12 highlighted pathways associated with survival, proliferation, and differentiation. Lair1 mice had reduced frequencies of Ly6C monocytes, which were associated with altered proliferation and apoptosis of non-classical monocytes from bone marrow and altered heterogeneity of interstitial macrophages in lung. Myeloid-specific LAIR1 deficiency promoted metastatic growth in a melanoma model and LAIR1 expression associated with improved clinical outcomes in human metastatic melanoma. Thus, monocytes and macrophages rely on LAIR1 sensing of stromal determinants for fitness and function, with relevance in homeostasis and disease.
Topics: Animals; Apoptosis; Bone Marrow; COS Cells; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Lineage; Cell Proliferation; Chlorocebus aethiops; Female; Homeostasis; Humans; Lung; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Myeloid Cells; Neoplasm Metastasis; Proteomics; Receptors, Immunologic; Signal Transduction
PubMed: 34260887
DOI: 10.1016/j.immuni.2021.06.012 -
Frontiers in Immunology 2023Myeloid cells play a critical role in the pathogenesis of Inflammatory Bowel Diseases (IBDs), including Ulcerative Colitis (UC) and Crohn's Disease (CD). Dysregulation...
INTRODUCTION
Myeloid cells play a critical role in the pathogenesis of Inflammatory Bowel Diseases (IBDs), including Ulcerative Colitis (UC) and Crohn's Disease (CD). Dysregulation of the JAK/STAT pathway is associated with many pathological conditions, including IBD. Suppressors Of Cytokine Signaling (SOCS) are a family of proteins that negatively regulate the JAK/STAT pathway. Our previous studies identified that mice lacking in myeloid cells developed a hyper-activated phenotype of macrophages and neutrophils in a pre-clinical model of Multiple Sclerosis.
METHODS
To better understand the function of myeloid cell in the pathogenesis of colitis, mice with deletion in myeloid cells ( ) were utilized in a DSS-induced colitis model.
RESULTS
Our results indicate that deficiency in myeloid cells leads to more severe colitis induced by DSS, which correlates with increased infiltration of monocytes and neutrophils in the colon and increased numbers of monocytes and neutrophils in the spleen. Furthermore, our results demonstrate that the expression of genes related to the pathogenesis and diagnosis of colitis such as , , and were specifically enhanced in -deficient neutrophils localized to the colon and spleen. Conversely, there were no observable differences in gene expression in Ly6C monocytes. Depletion of neutrophils using a neutralizing antibody to Ly6G significantly improved the disease severity of DSS-induced colitis in -deficient mice.
DISCUSSION
Thus, our results suggest that deficiency of in myeloid cells exacerbates DSS-induced colitis and that prevents overt activation of the immune system in IBD. This study may provide novel therapeutic strategies to IBD patients with hyperactivated neutrophils.
Topics: Mice; Animals; Dextran Sulfate; Janus Kinases; Signal Transduction; STAT Transcription Factors; Colitis; Suppressor of Cytokine Signaling Proteins; Inflammatory Bowel Diseases; Myeloid Cells; Suppressor of Cytokine Signaling 3 Protein
PubMed: 37283760
DOI: 10.3389/fimmu.2023.1163987 -
Trends in Cancer Oct 2022Glioblastoma (GBM) is the most aggressive and lethal form of brain tumor in human adults. Myeloid-lineage cells, including macrophages, microglia, myeloid-derived... (Review)
Review
Glioblastoma (GBM) is the most aggressive and lethal form of brain tumor in human adults. Myeloid-lineage cells, including macrophages, microglia, myeloid-derived suppressor cells (MDSCs), and neutrophils, are the most frequent types of cell in the GBM tumor microenvironment (TME) that contribute to tumor progression. Emerging experimental evidence indicates that symbiotic interactions between cancer cells and myeloid cells are critical for tumor growth and immunotherapy resistance in GBM. In this review, we discuss the molecular mechanisms whereby cancer cells shape a myeloid cell-mediated immunosuppressive TME and, reciprocally, how such myeloid cells affect tumor progression and immunotherapy efficiency in GBM. Moreover, we highlight tumor-T cell symbiosis and summarize immunotherapeutic strategies intercepting this co-dependency in GBM.
Topics: Brain Neoplasms; Glioblastoma; Humans; Myeloid-Derived Suppressor Cells; Symbiosis; Tumor Microenvironment
PubMed: 35624002
DOI: 10.1016/j.trecan.2022.04.010 -
Cell Reports Apr 2023Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the...
Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3, depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control.
Topics: Mice; Animals; Squamous Cell Carcinoma of Head and Neck; Fatty Acids; Interferon Type I; Myeloid Cells; Head and Neck Neoplasms; Tumor Microenvironment
PubMed: 36952341
DOI: 10.1016/j.celrep.2023.112303 -
International Journal of Molecular... Aug 2020Extracellular vesicles (EV) can carry proteins, RNA and DNA, thus serving as communication tools between cells. Tumor cells secrete EV, which can be taken up by... (Review)
Review
Extracellular vesicles (EV) can carry proteins, RNA and DNA, thus serving as communication tools between cells. Tumor cells secrete EV, which can be taken up by surrounding cells in the tumor microenvironment as well as by cells in distant organs. Tumor-derived EV (TEV) contain factors induced by tumor-associated hypoxia such as heat shock proteins or a variety of microRNA (miRNA). The interaction of TEV with tumor and host cells can promote cancer angiogenesis, invasion and metastasis. Myeloid cells are widely presented in tissues, comprise the majority of immune cells and play an essential role in immune reactions and tissue remodeling. However, in cancer, the differentiation of myeloid cells and their functions are impaired, resulting in tumor promotion. Such alterations are due to chronic inflammatory conditions associated with cancer and are mediated by the tumor secretome, including TEV. A high capacity of myeloid cells to clear EV from circulation put them in the central position in EV-mediated formation of pre-metastatic niches. The exposure of myeloid cells to TEV could trigger numerous signaling pathways. Progenitors of myeloid cells alter their differentiation upon the contact with TEV, resulting in the generation of myeloid-derived suppressor cells (MDSC), inhibiting anti-tumor function of T and natural killer (NK) cells and promoting thereby tumor progression. Furthermore, TEV can augment MDSC immunosuppressive capacity. Different subsets of mature myeloid cells such as monocytes, macrophages, dendritic cells (DC) and granulocytes take up TEV and acquire a protumorigenic phenotype. However, the delivery of tumor antigens to DC by TEV was shown to enhance their immunostimulatory capacity. The present review will discuss a diverse and complex EV-mediated crosstalk between tumor and myeloid cells in the context of the tumor type, TEV-associated cargo molecules and type of recipient cells.
Topics: Animals; Cell Differentiation; Extracellular Vesicles; Humans; Immune Tolerance; Killer Cells, Natural; Myeloid-Derived Suppressor Cells; Neoplasms; Tumor Microenvironment
PubMed: 32878277
DOI: 10.3390/ijms21176319 -
Cells Oct 2021Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new... (Review)
Review
Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new immunotherapies. The recent use of high-dimensional single-cell approaches, e.g., mass cytometry and single-cell RNA-sequencing (scRNA-seq) has reinforced the predominance of myeloid cells in the tumor microenvironment and uncovered their phenotypic diversity in different cancers. The cancerous metabolic environment has emerged as a critical modulator of myeloid cell functions in anti-tumor immunity versus immune suppression and immune evasion. Here, we discuss mechanisms of immune-metabolic crosstalk in tumorigenesis, with a particular focus on the tumor-associated myeloid cell's metabolic programs. We highlight the impact of several metabolic pathways on the pro-tumoral functions of tumor-associated macrophages and myeloid-derived suppressor cells and discuss the potential myeloid cell metabolic checkpoints for cancer immunotherapy, either as monotherapies or in combination with other immunotherapies.
Topics: Clinical Trials as Topic; Glycolysis; Humans; Lipid Metabolism; Myeloid Cells; Tumor Microenvironment; Wnt Proteins
PubMed: 34831183
DOI: 10.3390/cells10112960 -
The FEBS Journal Jan 2021The interface between the mammalian host and its environment is formed by barrier tissues, for example, of the skin, and the respiratory and the intestinal tracts. On... (Review)
Review
The interface between the mammalian host and its environment is formed by barrier tissues, for example, of the skin, and the respiratory and the intestinal tracts. On the one hand, barrier tissues are colonized by site-adapted microbial communities, and on the other hand, they contain specific myeloid cell networks comprising macrophages, dendritic cells, and granulocytes. These immune cells are tightly regulated in function and cell number, indicating important roles in maintaining tissue homeostasis and immune balance in the presence of commensal microorganisms. The regulation of myeloid cell density and activation involves cell-autonomous 'single-loop circuits' including autocrine mechanisms. However, an array of microenvironmental factors originating from nonimmune cells and the microbiota, as well as the microanatomical structure, impose additional layers of regulation onto resident myeloid cells. This review discusses models integrating these factors into cell-specific programs to instruct differentiation and proliferation best suited for the maintenance and renewal of immune homeostasis in the tissue-specific environment.
Topics: Animals; Autocrine Communication; Cell Count; Cell Differentiation; Cell Proliferation; Cytokines; Dendritic Cells; Granulocytes; Homeostasis; Humans; Immunity, Innate; Intestinal Mucosa; Macrophages; Microbiota; Models, Immunological; Respiratory Mucosa; Skin; Symbiosis
PubMed: 32502309
DOI: 10.1111/febs.15436 -
International Journal of Molecular... May 2021The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is... (Review)
Review
The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell markers. These good sentinel cells experience significant changes, facilitating glioblastoma development and protecting it from therapeutic treatments. Huge, complicated mechanisms are involved during the overall processes. A lot of effort has been dedicated to crack the mysterious codes in macrophage/microglia recruiting, activating, reprogramming, and functioning. We have made our path. With more and more key factors identified, a lot of new therapeutic methods could be explored to break the ominous loop, to enhance tumor sensitivity to treatments, and to improve the prognosis of glioblastoma patients. However, it might be a synergistic system rather than a series of clear, stepwise events. There are still significant challenges before the light of truth can shine onto the field. Here, we summarize recent advances in this field, reviewing the path we have been on and where we are now.
Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Macrophages; Microglia; Myeloid Cells; Prognosis; Signal Transduction; Tumor Microenvironment
PubMed: 34071306
DOI: 10.3390/ijms22115775