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Nature Immunology Mar 2017Myeloid cells in the central nervous system (CNS) represent a heterogeneous class of innate immune cells that contribute to the maintenance of tissue homeostasis... (Review)
Review
Myeloid cells in the central nervous system (CNS) represent a heterogeneous class of innate immune cells that contribute to the maintenance of tissue homeostasis differentially during development and adulthood. The subsets of CNS myeloid cells identified so far, including parenchymal microglia and non-parenchymal meningeal, perivascular and choroid-plexus macrophages, as well as disease-associated monocytes, have classically been distinguished on the basis of their surface epitope expression, localization and morphology. However, studies using cell-specific targeting, in vivo imaging, single-cell expression analysis and other sophisticated tools have now increased the depth of knowledge of this immune-cell compartment and call for reevaluation of the traditional views on the origin, fate and function of distinct CNS myeloid subsets. The concepts of CNS macrophage biology that are emerging from these new insights have broad implications for the understanding and treatment of CNS diseases.
Topics: Animals; Cell Differentiation; Central Nervous System; Central Nervous System Diseases; Gene Expression Regulation; Homeostasis; Humans; Immunity, Innate; Immunologic Surveillance; Macrophages; Microglia; Myeloid Cells
PubMed: 28323268
DOI: 10.1038/ni.3703 -
Current Opinion in Immunology Feb 2021Myeloid cells are components of the innate immune system that represent the first line of defense. Tissue damage, associated with pathological conditions such as... (Review)
Review
Myeloid cells are components of the innate immune system that represent the first line of defense. Tissue damage, associated with pathological conditions such as infection, cancer or autoimmunity, leads to the exposure of the intracellular content to the extracellular environment. Myeloid cells detect ligands exposed or released by dead cells through specific receptors that signal for a diversity of responses. Inflammatory responses triggered by myeloid cells after sensing tissue injury can contribute to resolution of the damage. The signaling response following dead-cell sensing by myeloid cells can contribute either to an inflammatory or a regulatory response. We review herein some representative examples of how myeloid cells react to the recognition of cell death during specific tissue damage contexts. A deep understanding of the cellular and molecular mechanisms underlying these processes would allow to improve therapeutical interventions in pathologies associated with tissue damage.
Topics: Animals; Cell Death; Humans; Immunity, Innate; Myeloid Cells; Signal Transduction
PubMed: 33035713
DOI: 10.1016/j.coi.2020.08.006 -
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 -
Immunology and Cell Biology Sep 2022Studies have highlighted a critical role for autophagy in the regulation of multiple cytokines. Autophagy inhibits the release of interleukin (IL)-1 family cytokines,...
Studies have highlighted a critical role for autophagy in the regulation of multiple cytokines. Autophagy inhibits the release of interleukin (IL)-1 family cytokines, including IL-1α, IL-1β and IL-18, by myeloid cells. This, in turn, impacts the release of other cytokines by myeloid cells, as well as other cells of the immune system, including IL-22, IL-23, IL-17 and interferon-γ. Here, we assessed the impact of genetic depletion of the autophagy gene Atg7 in myeloid cells on acute and chronic inflammation. In a model of acute lipopolysaccharide-induced endotoxemia, loss of autophagy in myeloid cells resulted in increased release of proinflammatory cytokines, both locally and systemically. By contrast, loss of Atg7 in myeloid cells in the Lyn model of lupus-like autoimmunity resulted in reduced systemic release of IL-6 and IL-10, with no effects on other cytokines observed. In addition, Lyn mice with autophagy-deficient myeloid cells showed reduced expression of autoantibodies relevant to systemic lupus erythematosus, including anti-histone and anti-Smith protein. In vitro, loss of autophagy, through pharmacological inhibition or small interfering RNA against Becn1, inhibited IL-10 release by human and mouse myeloid cells. This effect was evident at the level of Il10 messenger RNA expression. Our data highlight potentially important differences in the role of myeloid cell autophagy in acute and chronic inflammation and demonstrate a direct role for autophagy in the production and release of IL-10 by macrophages.
Topics: Animals; Autophagy; Cytokines; Humans; Inflammation; Interleukin-10; Mice; Myeloid Cells
PubMed: 35652357
DOI: 10.1111/imcb.12562 -
Microbiology Spectrum Nov 2016Myeloid cells make extensive use of the complement system in the context of recruitment, phagocytosis, and other effector functions. There are several types of... (Review)
Review
Myeloid cells make extensive use of the complement system in the context of recruitment, phagocytosis, and other effector functions. There are several types of complement receptors on myeloid cells, including G protein-coupled receptors for localizing the source of complement activation, and three sets of type I transmembrane proteins that link complement to phagocytosis: complement receptor 1, having an extracellular domain with tandem complement regulatory repeats; complement receptors 3 and 4, which are integrin family receptors comprising heterodimers of type I transmembrane subunits; and VSIG4, a member of the Ig superfamily. This review will focus on the role of the different classes of complement receptors and how their activities are integrated in the setting of immune tolerance and inflammatory responses.
Topics: Animals; Cell Adhesion; Humans; Myeloid Cells; Phagocytosis; Receptors, Complement
PubMed: 27809953
DOI: 10.1128/microbiolspec.MCHD-0034-2016 -
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 2023Colorectal cancer (CRC) is the third most predominant malignancy in the world. Although the importance of immune system in cancer development has been well established,...
Colorectal cancer (CRC) is the third most predominant malignancy in the world. Although the importance of immune system in cancer development has been well established, the underlying mechanisms remain to be investigated further. Here we studied a novel protein prokineticin 2 (Prok2, also known as Bv8) as a key pro-tumoral factor in CRC progression in and settings. Human colorectal tumor tissues, myeloid cell lines (U937 cells and HL60 cells) and colorectal cancer cell line (Caco-2 cells) were used for various studies. Myeloid cell infiltration (especially neutrophils) and Bv8 accumulation were detected in human colorectal tumor tissue with immunostaining. The chemotactic effects of Bv8 on myeloid cells were presented in the transwell assay and chemotaxis assy. Cultured CRC cells treated with myeloid cells or Bv8 produced reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF). Furthermore, ROS and VEGF acted as pro-angiogenesis buffer in myeloid cell-infiltrated CRC microenvironment. Moreover, myeloid cells or Bv8 enhanced energy consumption of glycolysis ATP and mitochondria ATP of CRC cells. Interestingly, myeloid cells increased CRC cell viability, but CRC cells decreased the viability of myeloid cells. ERK signalling pathway in CRC cells was activated in the presence of Bv8 or co-cultured myeloid cells. In conclusion, our data indicated the vital roles of Bv8 in myeloid cell infiltration and CRC development, suggesting that Bv8 may be a potential therapeutic target for colorectal cancer-related immunotherapy.
Topics: Humans; Vascular Endothelial Growth Factor A; Caco-2 Cells; Reactive Oxygen Species; Neuropeptides; Myeloid Cells; Cell Movement; Colorectal Neoplasms; Vascular Endothelial Growth Factors; Adenosine Triphosphate; Tumor Microenvironment
PubMed: 37090721
DOI: 10.3389/fimmu.2023.1158045 -
Nature Cell Biology Jun 2020PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor...
PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3-ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1β restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1β production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.
Topics: Animals; Antineoplastic Agents; Inflammasomes; Interleukin-1beta; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells; NLR Family, Pyrin Domain-Containing 3 Protein; PTEN Phosphohydrolase; Phosphorylation
PubMed: 32367047
DOI: 10.1038/s41556-020-0510-3 -
European Journal of Cancer (Oxford,... May 2017The success of cancer immunotherapy has generated tremendous interest in identifying new immunotherapeutic targets. To date, the majority of therapies have focussed on... (Review)
Review
The success of cancer immunotherapy has generated tremendous interest in identifying new immunotherapeutic targets. To date, the majority of therapies have focussed on stimulating the adaptive immune system to attack cancer, including agents targeting CTLA-4 and the PD-1/PD-L1 axis. However, macrophages and other myeloid immune cells offer much promise as effectors of cancer immunotherapy. The CD47/signal regulatory protein alpha (SIRPα) axis is a critical regulator of myeloid cell activation and serves a broader role as a myeloid-specific immune checkpoint. CD47 is highly expressed on many different types of cancer, and it transduces inhibitory signals through SIRPα on macrophages and other myeloid cells. In a diverse range of preclinical models, therapies that block the CD47/SIRPα axis stimulate phagocytosis of cancer cells in vitro and anti-tumour immune responses in vivo. A number of therapeutics that target the CD47/SIRPα axis are under preclinical and clinical investigation. These include anti-CD47 antibodies, engineered receptor decoys, anti-SIRPα antibodies and bispecific agents. These therapeutics differ in their pharmacodynamic, pharmacokinetic and toxicological properties. Clinical trials are underway for both solid and haematologic malignancies using anti-CD47 antibodies and recombinant SIRPα proteins. Since the CD47/SIRPα axis also limits the efficacy of tumour-opsonising antibodies, additional trials will examine their potential synergy with agents such as rituximab, cetuximab and trastuzumab. Phagocytosis in response to CD47/SIRPα-blocking agents results in antigen uptake and presentation, thereby linking the innate and adaptive immune systems. CD47/SIRPα blocking therapies may therefore synergise with immune checkpoint inhibitors that target the adaptive immune system. As a critical regulator of macrophage phagocytosis and activation, the potential applications of CD47/SIRPα blocking therapies extend beyond human cancer. They may be useful for the treatment of infectious disease, conditioning for stem cell transplant, and many other clinical indications.
Topics: Animals; Antibodies, Neoplasm; Antigen Presentation; Antigens, Differentiation; CD47 Antigen; Humans; Immunotherapy; Macrophages; Mice; Molecular Targeted Therapy; Myeloid Cells; Neoplasms; Phagocytosis; Receptors, Immunologic
PubMed: 28286286
DOI: 10.1016/j.ejca.2017.02.013