-
European Journal of Immunology Oct 2023Experimental autoimmune encephalomyelitis (EAE) is an animal model of central nervous system (CNS) autoimmunity. It is most commonly used to mimic aspects of multiple... (Review)
Review
Experimental autoimmune encephalomyelitis (EAE) is an animal model of central nervous system (CNS) autoimmunity. It is most commonly used to mimic aspects of multiple sclerosis (MS), a demyelinating disorder of the human brain and spinal cord. The innate immune response displays one of the core pathophysiological features linked to both the acute and chronic stages of MS. Hence, understanding and targeting the innate immune response is essential. Microglia and other CNS resident MUs, as well as infiltrating myeloid cells, diverge substantially in terms of both their biology and their roles in EAE. Recent advances in the field show that antigen presentation, as well as disease-propagating and regulatory interactions with lymphocytes, can be attributed to specific myeloid cell types and cell states in EAE lesions, following a distinct temporal pattern during disease initiation, propagation and recovery. Furthermore, single-cell techniques enable the assessment of characteristic proinflammatory as well as beneficial cell states, and identification of potential treatment targets. Here, we discuss the principles of EAE induction and protocols for varying experimental paradigms, the composition of the myeloid compartment of the CNS during health and disease, and systematically review effects on myeloid cells for therapeutic approaches in EAE.
Topics: Animals; Humans; Mice; Encephalomyelitis, Autoimmune, Experimental; Central Nervous System; Multiple Sclerosis; Spinal Cord; Myeloid Cells; Mice, Inbred C57BL
PubMed: 37505465
DOI: 10.1002/eji.202250234 -
The Journal of Experimental Medicine Sep 2021Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic...
Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.
Topics: Aged; Animals; Basic Helix-Loop-Helix Transcription Factors; Cardiomyopathies; Disease Models, Animal; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Macrophages; Male; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Myeloid Cells; Myocardial Infarction; Myocardial Ischemia; Myocarditis; Mice
PubMed: 34325467
DOI: 10.1084/jem.20200667 -
European Journal of Cancer (Oxford,... Jul 2023Despite over a decade of clinical trials combining inhibition of emerging checkpoints with a PD-1/L1 inhibitor backbone, meaningful survival benefits have not been shown... (Review)
Review
Despite over a decade of clinical trials combining inhibition of emerging checkpoints with a PD-1/L1 inhibitor backbone, meaningful survival benefits have not been shown in PD-1/L1 inhibitor resistant or refractory solid tumours, particularly tumours dominated by a myelosuppressive microenvironment. Achieving durable anti-tumour immunity will therefore likely require combination of adaptive and innate immune stimulation, myeloid repolarisation, enhanced APC activation and antigen processing/presentation, lifting of the CD47/SIRPα (Cluster of Differentiation 47/signal regulatory protein alpha) 'do not eat me' signal, provision of an apoptotic 'pro-eat me' or 'find me' signal, and blockade of immune checkpoints. The importance of effectively targeting mLILRB2 and SIRPAyeloid cells to achieve improved response rates has recently been emphasised, given myeloid cells are abundant in the tumour microenvironment of most solid tumours. TNFSF14, or LIGHT, is a tumour necrosis superfamily ligand with a broad range of adaptive and innate immune activities, including (1) myeloid cell activation through Lymphotoxin Beta Receptor (LTβR), (2) T/NK (T cell and natural killer cell) induced anti-tumour immune activity through Herpes virus entry mediator (HVEM), (3) potentiation of proinflammatory cytokine/chemokine secretion through LTβR on tumour stromal cells, (4) direct induction of tumour cell apoptosis in vitro, and (5) the reorganisation of lymphatic tissue architecture, including within the tumour microenvironment (TME), by promoting high endothelial venule (HEV) formation and induction of tertiary lymphoid structures. LTBR (Lymphotoxin beta receptor) and HVEM rank highly amongst a range of costimulatory receptors in solid tumours, which raises interest in considering how LIGHT-mediated costimulation may be distinct from a growing list of immunotherapy targets which have failed to provide survival benefit as monotherapy or in combination with PD-1 inhibitors, particularly in the checkpoint acquired resistant setting.
Topics: Humans; Lymphotoxin beta Receptor; Programmed Cell Death 1 Receptor; Myeloid Cells; Cytokines; Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37167762
DOI: 10.1016/j.ejca.2023.03.040 -
Advances in Immunology 2023Myeloid cells, particularly macrophages, act as the frontline responders to infectious agents and initiate inflammation. While the molecular mechanisms driving... (Review)
Review
Myeloid cells, particularly macrophages, act as the frontline responders to infectious agents and initiate inflammation. While the molecular mechanisms driving inflammatory responses have primarily focused on pattern recognition by myeloid cells and subsequent transcriptional events, it is crucial to note that post-transcriptional regulation plays a pivotal role in this process. In addition to the transcriptional regulation of innate immune responses, additional layers of intricate network of post-transcriptional mechanisms critically determine the quantity and duration of key inflammatory products and thus the outcome of immune responses. A multitude of mechanisms governing post-transcriptional regulation in innate immunity have been uncovered, encompassing RNA alternative splicing, mRNA stability, and translational regulation. This review encapsulates the current insights into the post-transcriptional regulation of inflammatory genes within myeloid cells, with particular emphasis on translational regulation during inflammation. While acknowledging the advancements, we also shed light on the existing gaps in immunological research pertaining to post-transcriptional levels and propose perspectives that controlling post-transcriptional process may serve as potential targets for therapeutic interventions in inflammatory diseases.
Topics: Humans; Immunity, Innate; Inflammation; Myeloid Cells; Macrophages; Alternative Splicing
PubMed: 38042586
DOI: 10.1016/bs.ai.2023.09.001 -
Frontiers in Immunology 2020Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient... (Review)
Review
Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.
Topics: Animals; Antineoplastic Agents; Arginase; Arginine; Clinical Trials as Topic; Humans; Macrophages; Mice; Myeloid Cells; Myeloid Progenitor Cells; Neoplasms
PubMed: 32499785
DOI: 10.3389/fimmu.2020.00938 -
Nature Communications Nov 2023Disease-modifying therapies (DMTs) are widely used in neuroimmunological diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD)....
Disease-modifying therapies (DMTs) are widely used in neuroimmunological diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Although these treatments are known to predispose patients to infections and affect their responses to vaccination, little is known about the impact of DMTs on the myeloid cell compartment. In this study, we use mass cytometry to examine DMT-associated changes in the innate immune system in untreated and treated patients with MS (n = 39) or NMOSD (n = 23). We also investigated the association between changes in myeloid cell phenotypes and longitudinal responsiveness to homologous primary, secondary, and tertiary SARS-CoV-2 mRNA vaccinations. Multiple DMT-associated myeloid cell clusters, in particular CD64HLADR granulocytes, showed significant correlations with B and T cell responses induced by vaccination. Our findings suggest the potential role of myeloid cells in cellular and humoral responses following vaccination in DMT-treated patients with neuroimmunological diseases.
Topics: Humans; Myeloid Cells; Granulocytes; Myeloid Progenitor Cells; Vaccination; Multiple Sclerosis; Neuromyelitis Optica; Antibodies, Viral
PubMed: 38007484
DOI: 10.1038/s41467-023-43553-z -
Journal of Leukocyte Biology Nov 2022In addition to CD4+ T lymphocytes, cells of the myeloid lineage such as macrophages, dendritic cells (DCs), and osteoclasts (OCs) are emerging as important target cells... (Review)
Review
In addition to CD4+ T lymphocytes, cells of the myeloid lineage such as macrophages, dendritic cells (DCs), and osteoclasts (OCs) are emerging as important target cells for HIV-1, as they likely participate in all steps of pathogenesis, including sexual transmission and early virus dissemination in both lymphoid and nonlymphoid tissues where they can constitute persistent virus reservoirs. At least in vitro, these myeloid cells are poorly infected by cell-free viral particles. In contrast, intercellular virus transmission through direct cell-to-cell contacts may be a predominant mode of virus propagation in vivo leading to productive infection of these myeloid target cells. HIV-1 cell-to-cell transfer between CD4+ T cells mainly through the formation of the virologic synapse, or from infected macrophages or dendritic cells to CD4+ T cell targets, have been extensively described in vitro. Recent reports demonstrate that myeloid cells can be also productively infected through virus homotypic or heterotypic cell-to-cell transfer between macrophages or from virus-donor-infected CD4+ T cells, respectively. These modes of infection of myeloid target cells lead to very efficient spreading in these poorly susceptible cell types. Thus, the goal of this review is to give an overview of the different mechanisms reported in the literature for cell-to-cell transfer and spreading of HIV-1 in myeloid cells.
Topics: Humans; HIV-1; CD4-Positive T-Lymphocytes; Myeloid Cells; Macrophages; HIV Infections; Dendritic Cells
PubMed: 35355323
DOI: 10.1002/JLB.4MR0322-737R -
Frontiers in Immunology 2022The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and... (Review)
Review
The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and understanding of these tumors. Single cell analysis techniques such as single cell genomic and transcriptomic sequencing analysis are on the rise and play an important role in elucidating the glioma TME. These large datasets will prove useful for patient tumor characterization, including immune configuration that will ultimately influence therapeutic choices and especially immune therapies. In this review we discuss the advantages and drawbacks of these techniques while debating their role in the domain of glioma-infiltrating myeloid cells characterization and function.
Topics: Glioblastoma; Glioma; Humans; Myeloid Cells; Myeloid Progenitor Cells; Tumor Microenvironment
PubMed: 35784281
DOI: 10.3389/fimmu.2022.907605 -
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 -
Cellular & Molecular Immunology Mar 2021Myeloid cells in tumor tissues constitute a dynamic immune population characterized by a non-uniform phenotype and diverse functional activities. Both tumor-associated... (Review)
Review
Myeloid cells in tumor tissues constitute a dynamic immune population characterized by a non-uniform phenotype and diverse functional activities. Both tumor-associated macrophages (TAMs), which are more abundantly represented, and tumor-associated neutrophils (TANs) are known to sustain tumor cell growth and invasion, support neoangiogenesis and suppress anticancer adaptive immune responses. In recent decades, several therapeutic approaches have been implemented in preclinical cancer models to neutralize the tumor-promoting roles of both TAMs and TANs. Some of the most successful strategies have now reached the clinic and are being investigated in clinical trials. In this review, we provide an overview of the recent literature on the ever-growing complexity of the biology of TAMs and TANs and the development of the most promising approaches to target these populations therapeutically in cancer patients.
Topics: Animals; Humans; Immunotherapy; Myeloid Cells; Neoplasms; Neutrophils; Tumor-Associated Macrophages
PubMed: 33473192
DOI: 10.1038/s41423-020-00613-4