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Cellular and Molecular Gastroenterology... 2019Pancreatitis is a major cause of morbidity and mortality and is a risk factor for pancreatic tumorigenesis. Upon tissue damage, an inflammatory response, made up largely...
BACKGROUND & AIMS
Pancreatitis is a major cause of morbidity and mortality and is a risk factor for pancreatic tumorigenesis. Upon tissue damage, an inflammatory response, made up largely of macrophages, provides multiple growth factors that promote repair. Here, we examine the molecular pathways initiated by macrophages to promote pancreas recovery from pancreatitis.
METHODS
To induce organ damage, mice were subjected to cerulein-induced experimental pancreatitis and analyzed at various times of recovery. CD11b-DTR mice were used to deplete myeloid cells. Hbegf;LysM-Cre mice were used to ablate myeloid cell-derived heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF). To ablate EGFR specifically during recovery, pancreatitis was induced in Egfr;Ptf1a;FSF-Rosa26 mice followed by tamoxifen treatment.
RESULTS
Macrophages infiltrating the pancreas in experimental pancreatitis make high levels of HB-EGF. Both depletion of myeloid cells and ablation of myeloid cell HB-EGF delayed recovery from experimental pancreatitis, resulting from a decrease in cell proliferation and an increase in apoptosis. Mechanistically, ablation of myeloid cell HB-EGF impaired epithelial cell DNA repair, ultimately leading to cell death. Soluble HB-EGF induced EGFR nuclear translocation and methylation of histone H4, facilitating resolution of DNA damage in pancreatic acinar cells in vitro. Consistent with its role as the primary receptor of HB-EGF, in vivo ablation of EGFR from pancreatic epithelium during recovery from pancreatitis resulted in accumulation of DNA damage.
CONCLUSIONS
By using novel conditional knockout mouse models, we determined that HB-EGF derived exclusively from myeloid cells induces epithelial cell proliferation and EGFR-dependent DNA repair, facilitating pancreas healing after injury.
Topics: Animals; DNA; DNA Repair; Heparin-binding EGF-like Growth Factor; Mice; Mice, Knockout; Myeloid Cells; Pancreas; Pancreatitis; Regeneration
PubMed: 31125624
DOI: 10.1016/j.jcmgh.2019.05.006 -
Neuropathology and Applied Neurobiology Feb 2023Glioblastomas are high-grade brain tumours that are characterised by the accumulation of brain-resident microglia and peripheral macrophages. Recruitment of these...
AIMS
Glioblastomas are high-grade brain tumours that are characterised by the accumulation of brain-resident microglia and peripheral macrophages. Recruitment of these myeloid cells can be facilitated by CCR2/CCL2 signalling. Besides the well-known CCR2 macrophages, we have identified microglia expressing CCR2 in glioma tissues. Thus, we investigated how Ccr2-deficiency of one of the myeloid cell populations affects the other population and tumour biology.
METHODS
We generated four chimeric groups to analyse single and combined Ccr2-deficiency of microglia and macrophages. On day 21 after tumour cell implantation (GL261), we conducted flow cytometry, immunofluorescence and real-time polymerase chain reaction analyses. Tumour volume and metabolism were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Moreover, in vitro studies were performed with primary microglia and bone marrow-derived macrophages.
RESULTS
We demonstrated reduced infiltration of macrophages and microglia depending on the lack of Ccr2. However, the total number of myeloid cells remained constant except for the animals with dual Ccr2-knockout. Both microglia and macrophages with Ccr2-deficiency showed impaired expression of proinflammatory molecules and altered phagocytic activity. Despite the altered immunologic phenotype caused by Ccr2-deficiency, glioma progression and metabolism were hardly affected. Alterations were detected solely in apoptosis and proliferation of tumours from animals with specific Ccr2-deficient microglia, whereas vessel stability was increased in mice with Ccr2-knockout in both cell populations.
CONCLUSION
These results indicate that microglia and macrophages provide a homoeostatic balance within glioma tissue and compensate for the lack of the corresponding counterpart. Moreover, we identified that the CCR2/CCL2 axis is involved in the immunologic function of microglia and macrophages beyond its relevance for migration.
Topics: Mice; Animals; Glioblastoma; Mice, Transgenic; Myeloid Cells; Macrophages; Microglia; Glioma; Mice, Inbred C57BL; Receptors, CCR2
PubMed: 36346010
DOI: 10.1111/nan.12863 -
Seminars in Immunology Aug 2014Diabetes can promote a state of chronic inflammation associated with serious complications that are difficult to treat, including ulceration of the lower extremities and... (Review)
Review
Diabetes can promote a state of chronic inflammation associated with serious complications that are difficult to treat, including ulceration of the lower extremities and chronic wounds. Chronic wounds are often incurable and contribute to both a reduced quality of life for patients and an enormous burden for healthcare services. In diabetes, the inflammatory response early in wound healing is inappropriately amplified and prolonged, leading to the persistent presence in the wound of vastly elevated numbers of dysfunctional, hyperpolarised macrophages that fail to transition to a pro-healing phenotype. Recent evidence suggests that systemic chronic inflammation induces intrinsic defects in monocytes via chromatin modifications that may pre-programme monocytes to a pro-inflammatory phenotype, while the local wound environment inhibits differentiation to a pro-healing phenotype. Current understanding remains incomplete, and careful dissection of how local and systemic inflammation combine to negatively influence myeloid cell development will be key to developing effective therapies aimed at healing the diabetic wound.
Topics: Animals; Diabetes Complications; Humans; Inflammation; Mice; Myeloid Cells; Wound Healing
PubMed: 24954378
DOI: 10.1016/j.smim.2014.04.006 -
Energy metabolism drives myeloid-derived suppressor cell differentiation and functions in pathology.Journal of Leukocyte Biology Aug 2017Over the last decade, a heterogeneous population of immature myeloid cells with major regulatory functions has been described in cancer and other pathologic conditions... (Review)
Review
Over the last decade, a heterogeneous population of immature myeloid cells with major regulatory functions has been described in cancer and other pathologic conditions and ultimately defined as MDSCs. Most of the early work on the origins and functions of MDSCs has been in murine and human tumor bearers in which MDSCs are known to be immunosuppressive and to result in both reduced immune surveillance and antitumor cytotoxicity. More recent studies, however, suggest that expansion of these immature myeloid cells may be linked to most, if not all, chronic and acute inflammatory processes. The universal expansion to inflammatory stimuli of MDSCs suggests that these cells may be more of a normal component of the inflammatory response (emergency myelopoiesis) than simply a pathologic response to a growing tumor. Instead of an adverse immunosuppressive response, expansion of these immature myeloid cell populations may result from a complex balance between increased immune surveillance and dampened adaptive immune responses that are common to many inflammatory responses. Within this scenario, new pathways of metabolic reprogramming are emerging as drivers of MDSC differentiation and functions in cancer and inflammatory disorders, crucially linking metabolic syndrome to inflammatory processes.
Topics: Animals; Cell Differentiation; Energy Metabolism; Humans; Myeloid-Derived Suppressor Cells
PubMed: 28223316
DOI: 10.1189/jlb.4MR1116-476R -
Microbiology Spectrum Aug 2016Inflammation furnishes a series of pathogenic pathways that couple the risk factors for atherosclerosis with altered behavior of the intrinsic cells of the arterial... (Review)
Review
Inflammation furnishes a series of pathogenic pathways that couple the risk factors for atherosclerosis with altered behavior of the intrinsic cells of the arterial wall, endothelium, and smooth muscle and promote the disease and its complications. Myeloid cells participate critically in all phases of atherosclerosis from initiation through progression, and ultimately the thrombotic consequences of this disease. Foam cells, lipid-laden macrophages, constitute the hallmark of atheromata. Much of the recent expansion in knowledge of the roles of myeloid cells in atherosclerosis revolves around the functional contributions of subsets of monocytes, precursors of macrophages, the most abundant myeloid cells in the atheroma. Proinflammatory monocytes preferentially accumulate in nascent atherosclerotic plaques. The most dramatic manifestations of atherosclerosis result from blood clot formation. Myocardial infarction, ischemic stroke, and abrupt limb ischemia all arise primarily from thrombi that complicate atherosclerotic plaques. Myeloid cells contribute pivotally to triggering thrombosis, for example, by elaborating enzymes that degrade the plaque's protective extracellular matrix, rendering it fragile, and by producing the potent procoagulant tissue factor. While most attention has focused on mononuclear phagocytes, the participation of polymorphonuclear leukocytes may aggravate local thrombus formation. Existing therapies such as statins may exert some of their protective effects by altering the functions of myeloid cells. The pathways of innate immunity that involve myeloid cells provide a myriad of potential targets for modifying atherosclerosis and its complications, and provide a fertile field for future attempts to address the residual burden of this disease, whose global prevalence is on the rise.
Topics: Animals; Atherosclerosis; Humans; Myeloid Cells; Thrombosis
PubMed: 27726819
DOI: 10.1128/microbiolspec.MCHD-0026-2015 -
Cancer Letters May 2007Tumor growth and metastasis depend on neovascularization, the growth of new blood vessels. Recent findings have revealed that tumor neovascularization is regulated in... (Review)
Review
Tumor growth and metastasis depend on neovascularization, the growth of new blood vessels. Recent findings have revealed that tumor neovascularization is regulated in part by monocytes, which are myeloid lineage cells from the bone marrow. Tumors exhibit significant monocyte infiltrates, which are actively recruited to the tumor microenvironment. Upon tumor infiltration, monocytes can participate in tumor neovascularization. Monocytes can either differentiate into macrophages, which express proangiogenic growth factors, or into endothelial-like cells, which may directly participate in neovascularization. Preliminary studies in animals suggest that modulation of bone marrow-derived cell trafficking into tumors will provide a useful new approach in cancer therapy.
Topics: Animals; Cell Differentiation; Cell Movement; Endothelium, Vascular; Hematopoietic Stem Cells; Humans; Integrins; Macrophages; Models, Biological; Monocytes; Myeloid Cells; Neoplasms; Neovascularization, Pathologic
PubMed: 17049723
DOI: 10.1016/j.canlet.2006.09.002 -
International Immunology Mar 2021An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in...
An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.
Topics: COVID-19; Humans; Interleukin-8; Japan; Leukocyte Count; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neutrophil Activation; Neutrophils; SARS-CoV-2
PubMed: 33538817
DOI: 10.1093/intimm/dxab005 -
Frontiers in Immunology 2021Kidney transplantation is a primary therapy for end-stage renal disease (ESRD) all the time. But it does not mean that we have fully unraveling the mystery of kidney... (Review)
Review
Kidney transplantation is a primary therapy for end-stage renal disease (ESRD) all the time. But it does not mean that we have fully unraveling the mystery of kidney transplantation and confer every patient favorable prognosis. Immune rejection has always been a stumbling block when we try to increase the success rate of kidney transplantation and improve long-term outcomes. Even if the immune rejection is effectively controlled in acute phase, there is a high possibility that the immune response mediated by chronically activated antibodies will trigger chronic rejection and ultimately lead to graft failure. At present, immunosuppressive agent prepared chemically is mainly used to prevent acute or chronic rejection, but it failed to increase the long-term survival rate of allografts or reduce the incidence of chronic rejection after acute rejection, and is accompanied by many adverse reactions. Therefore, many studies have begun to use immune cells to regulate the immune response in order to control allograft rejection. This article will focus on the latest study and prospects of more popular regulatory myeloid cells in the direction of renal transplantation immunotherapy and introduce their respective progress from experimental research to clinical research.
Topics: Adoptive Transfer; Animals; Dendritic Cells; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Macrophages; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myeloid Cells; Treatment Outcome
PubMed: 33717141
DOI: 10.3389/fimmu.2021.625998 -
Journal of Autoimmunity Jun 2021Current treatment for patients with autoimmune disorders including rheumatoid arthritis, multiple sclerosis and type 1 diabetes, often consists of long-term drug... (Review)
Review
Current treatment for patients with autoimmune disorders including rheumatoid arthritis, multiple sclerosis and type 1 diabetes, often consists of long-term drug regimens that broadly dampen immune responses. These non-specific treatments are frequently associated with severe side effects creating an urgent need for safer and more effective therapy to promote peripheral tolerance in autoimmune diseases. Cell-based immunotherapy may offer an encouraging alternative, where tolerogenic CD14 myeloid cells are infused to inhibit autoreactive effector cells. In this review, we compared in depth three promising tolerogenic CD14 candidates for the treatment of autoimmune disease: 1) tolerogenic dendritic cells, 2) monocytic myeloid-derived suppressor cells and 3) CD14 type 2 conventional dendritic cells. TolDC-based therapy has entered clinical testing whereas evidence from the latter two cell types m-MDSCs and CD14 cDC2s is predominantly coming from cancer immunology research. These three cell types have distinct cellular properties and immunosuppressive mechanisms offering unique opportunities to be explored. However, these cells differ in stage of development towards immunotherapy each facing additional hurdles. Therefore, we speculate on the potential benefits and risks of these cell types as novel cell-based immunotherapies to control autoimmune disease in patients.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Biomarkers; Clinical Studies as Topic; Combined Modality Therapy; Dendritic Cells; Disease Management; Disease Models, Animal; Disease Susceptibility; Humans; Immune Tolerance; Lipopolysaccharide Receptors; Monocytes; Myeloid Cells; Myeloid-Derived Suppressor Cells; Treatment Outcome
PubMed: 33901801
DOI: 10.1016/j.jaut.2021.102645 -
Nature Reviews. Immunology Jan 2015Myeloid cells are crucial effectors of the innate immune response and important regulators of adaptive immunity. The differentiation and activation of myeloid cells... (Review)
Review
Myeloid cells are crucial effectors of the innate immune response and important regulators of adaptive immunity. The differentiation and activation of myeloid cells requires the timely regulation of gene expression; this depends on the interplay of a variety of elements, including transcription factors and epigenetic mechanisms. Epigenetic control involves histone modifications and DNA methylation, and is coupled to lineage-specifying transcription factors, upstream signalling pathways and external factors released in the bone marrow, blood and tissue environments. In this Review, we highlight key epigenetic events controlling myeloid cell biology, focusing on those related to myeloid cell differentiation, the acquisition of myeloid identity and innate immune memory.
Topics: Animals; Cell Differentiation; Epigenesis, Genetic; Epigenomics; Gene Expression Regulation; Humans; Immunity; Inflammation; Myeloid Cells; Myelopoiesis; Phenotype
PubMed: 25534619
DOI: 10.1038/nri3777