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Cell Metabolism Dec 2021Apoptotic cell clearance by macrophages (efferocytosis) promotes resolution signaling pathways, which can be triggered by molecules derived from the phagolysosomal...
Apoptotic cell clearance by macrophages (efferocytosis) promotes resolution signaling pathways, which can be triggered by molecules derived from the phagolysosomal degradation of apoptotic cells. We show here that nucleotides derived from the hydrolysis of apoptotic cell DNA by phagolysosomal DNase2a activate a DNA-PKcs-mTORC2/Rictor pathway that increases Myc to promote non-inflammatory macrophage proliferation. Efferocytosis-induced proliferation expands the pool of resolving macrophages in vitro and in mice, including zymosan-induced peritonitis, dexamethasone-induced thymocyte apoptosis, and atherosclerosis regression. In the dexamethasone-thymus model, hematopoietic Rictor deletion blocked efferocytosing macrophage proliferation, apoptotic cell clearance, and tissue resolution. In atherosclerosis regression, silencing macrophage Rictor or DNase2a blocked efferocyte proliferation, apoptotic cell clearance, and plaque stabilization. In view of previous work showing that other types of apoptotic cell cargo can promote resolution in individual efferocytosing macrophages, the findings here suggest that signaling-triggered apoptotic cell-derived nucleotides can amplify this benefit by increasing the number of these macrophages.
Topics: Animals; Apoptosis; Cell Proliferation; Macrophages; Mice; Mice, Inbred C57BL; Phagocytosis
PubMed: 34784501
DOI: 10.1016/j.cmet.2021.10.015 -
Neuron Nov 2022Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer's disease (AD) risk. In particular, AD... (Review)
Review
Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer's disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches.
Topics: Humans; Microglia; Alzheimer Disease; Genome-Wide Association Study; Gene Pool; Phagocytosis
PubMed: 36327897
DOI: 10.1016/j.neuron.2022.10.015 -
Nature Neuroscience Sep 2022Microglia are emerging as key drivers of neurological diseases. However, we lack a systematic understanding of the underlying mechanisms. Here, we present a screening...
Microglia are emerging as key drivers of neurological diseases. However, we lack a systematic understanding of the underlying mechanisms. Here, we present a screening platform to systematically elucidate functional consequences of genetic perturbations in human induced pluripotent stem cell-derived microglia. We developed an efficient 8-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. We established inducible CRISPR interference and activation in this system and conducted three screens targeting the 'druggable genome'. These screens uncovered genes controlling microglia survival, activation and phagocytosis, including neurodegeneration-associated genes. A screen with single-cell RNA sequencing as the readout revealed that these microglia adopt a spectrum of states mirroring those observed in human brains and identified regulators of these states. A disease-associated state characterized by osteopontin (SPP1) expression was selectively depleted by colony-stimulating factor-1 (CSF1R) inhibition. Thus, our platform can systematically uncover regulators of microglial states, enabling their functional characterization and therapeutic targeting.
Topics: Brain; Clustered Regularly Interspaced Short Palindromic Repeats; Humans; Induced Pluripotent Stem Cells; Microglia; Phagocytosis
PubMed: 35953545
DOI: 10.1038/s41593-022-01131-4 -
Nature Metabolism Mar 2023Resolving-type macrophages prevent chronic inflammation by clearing apoptotic cells through efferocytosis. These macrophages are thought to rely mainly on oxidative...
Resolving-type macrophages prevent chronic inflammation by clearing apoptotic cells through efferocytosis. These macrophages are thought to rely mainly on oxidative phosphorylation, but emerging evidence suggests a possible link between efferocytosis and glycolysis. To gain further insight into this issue, we investigated molecular-cellular mechanisms involved in efferocytosis-induced macrophage glycolysis and its consequences. We found that efferocytosis promotes a transient increase in macrophage glycolysis that is dependent on rapid activation of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), which distinguishes this process from glycolysis in pro-inflammatory macrophages. Mice transplanted with activation-defective PFKFB2 bone marrow and then subjected to dexamethasone-induced thymocyte apoptosis exhibit impaired thymic efferocytosis, increased thymic necrosis, and lower expression of the efferocytosis receptors MerTK and LRP1 on thymic macrophages compared with wild-type control mice. In vitro mechanistic studies revealed that glycolysis stimulated by the uptake of a first apoptotic cell promotes continual efferocytosis through lactate-mediated upregulation of MerTK and LRP1. Thus, efferocytosis-induced macrophage glycolysis represents a unique metabolic process that sustains continual efferocytosis in a lactate-dependent manner. The differentiation of this process from inflammatory macrophage glycolysis raises the possibility that it could be therapeutically enhanced to promote efferocytosis and resolution in chronic inflammatory diseases.
Topics: Animals; Mice; c-Mer Tyrosine Kinase; Inflammation; Lactic Acid; Macrophages; Phagocytosis
PubMed: 36797420
DOI: 10.1038/s42255-023-00736-8 -
Journal of Cerebral Blood Flow and... Sep 2022Stroke, including ischemic stroke and hemorrhagic stroke can cause massive neuronal death and disruption of brain structure, which is followed by secondary inflammatory...
Stroke, including ischemic stroke and hemorrhagic stroke can cause massive neuronal death and disruption of brain structure, which is followed by secondary inflammatory injury initiated by pro-inflammatory molecules and cellular debris. Phagocytic clearance of cellular debris by microglia, the brain's scavenger cells, is pivotal for neuroinflammation resolution and neurorestoration. However, microglia can also exacerbate neuronal loss by phagocytosing stressed-but-viable neurons in the penumbra, thereby expanding the injury area and hindering neurofunctional recovery. Microglia constantly patrol the central nervous system using their processes to scour the cellular environment and start or cease the phagocytosis progress depending on the "eat me" or "don't eat me'' signals on cellular surface. An optimal immune response requires a delicate balance between different phenotypic states to regulate neuro-inflammation and facilitate reconstruction after stroke. Here, we examine the literature and discuss the molecular mechanisms and cellular pathways regulating microglial phagocytosis, their resulting effects in brain injury and neural regeneration, as well as the potential therapeutic targets that might modulate microglial phagocytic activity to improve neurological function after stroke.
Topics: Brain Ischemia; Humans; Microglia; Neurons; Phagocytosis; Stroke
PubMed: 35491825
DOI: 10.1177/0271678X221098841 -
Frontiers in Immunology 2020Efficient inflammation resolution is important not only for the termination of the inflammatory response but also for the restoration of tissue integrity. An integral... (Review)
Review
Efficient inflammation resolution is important not only for the termination of the inflammatory response but also for the restoration of tissue integrity. An integral process to resolution of inflammation is the phagocytosis of dying cells by macrophages, known as efferocytosis. This function is mediated by a complex and well-orchestrated network of interactions amongst specialized phagocytic receptors, bridging molecules, as well as "find-me" and "eat-me" signals. Efferocytosis serves not only as a waste disposal mechanism (clearance of the apoptotic cells) but also promotes a pro-resolving phenotype in efferocytic macrophages and thereby termination of inflammation. Alterations in cellular metabolism are critical for shaping the phenotype and function of efferocytic macrophages, thus, representing an important determinant of macrophage plasticity. Impaired efferocytosis can result in inflammation-associated pathologies or autoimmunity. The present mini review summarizes current knowledge regarding the mechanisms regulating macrophage efferocytosis during clearance of inflammation.
Topics: Animals; Apoptosis; Humans; Inflammation; Macrophages; Phagocytosis
PubMed: 32296442
DOI: 10.3389/fimmu.2020.00553 -
Frontiers in Immunology 2021Microglia are the resident immune cells of the central nervous system that exert diverse roles in the pathogenesis of ischemic stroke. During the past decades,... (Review)
Review
Microglia are the resident immune cells of the central nervous system that exert diverse roles in the pathogenesis of ischemic stroke. During the past decades, microglial polarization and chemotactic properties have been well-studied, whereas less attention has been paid to phagocytic phenotypes of microglia in stroke. Generally, whether phagocytosis mediated by microglia plays a beneficial or detrimental role in stroke remains controversial, which calls for further investigations. Most researchers are in favor of the former proposal currently since efficient clearance of tissue debris promotes tissue reconstruction and neuronal network reorganization in part. Other scholars propose that excessively activated microglia engulf live or stressed neuronal cells, which results in neurological deficits and brain atrophy. Upon ischemia challenge, the microglia infiltrate injured brain tissue and engulf live/dead neurons, myelin debris, apoptotic cell debris, endothelial cells, and leukocytes. Cell phagocytosis is provoked by the exposure of "eat-me" signals or the loss of "dont eat-me" signals. We supposed that microglial phagocytosis could be initiated by the specific "eat-me" signal and its corresponding receptor on the specific cell type under pathological circumstances. In this review, we will summarize phagocytic characterizations of microglia after stroke and the potential receptors responsible for this programmed biological progress. Understanding these questions precisely may help to develop appropriate phagocytic regulatory molecules, which are promoting self-limiting inflammation without damaging functional cells.
Topics: Animals; Humans; Ischemic Stroke; Microglia; Phagocytosis
PubMed: 35082781
DOI: 10.3389/fimmu.2021.790201 -
Biomedicine & Pharmacotherapy =... Sep 2023Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in the loss of cognitive ability and memory. However, there is no specific treatment to... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in the loss of cognitive ability and memory. However, there is no specific treatment to mechanistically inhibit the progression of Alzheimer's disease, and most drugs only provide symptom relief and do not fundamentally reverse AD. Current studies show that triggering receptor expressed on myeloid cells 2 (TREM2) is predominantly expressed in microglia of the central nervous system (CNS) and is involved in microglia proliferation, survival, migration and phagocytosis. The current academic view suggests that TREM2 and its ligands have CNS protective effects in AD. Specifically, TREM2 acts by regulating the function of microglia and promoting the clearance of neuronal toxic substances and abnormal proteins by microglia. In addition, TREM2 is also involved in regulating inflammatory response and cell signaling pathways, affecting the immune response and regulatory role of microglia. Although the relationship between TREM2 and Alzheimer's disease has been extensively studied, its specific mechanism of action is not fully understood. The purpose of this review is to provide a comprehensive analysis of the research of TREM2, including its regulation of the inflammatory response, lipid metabolism and phagocytosis in microglia of CNS in AD, and to explore the potential application prospects as well as limitations of targeting TREM2 for the treatment of AD.
Topics: Humans; Alzheimer Disease; Microglia; Neurodegenerative Diseases; Central Nervous System; Phagocytosis; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37517293
DOI: 10.1016/j.biopha.2023.115218 -
Cancer Cell Apr 2021Immunotherapy induces durable clinical responses in a fraction of patients with cancer. However, therapeutic resistance poses a major challenge to current...
Immunotherapy induces durable clinical responses in a fraction of patients with cancer. However, therapeutic resistance poses a major challenge to current immunotherapies. Here, we identify that expression of tumor stanniocalcin 1 (STC1) correlates with immunotherapy efficacy and is negatively associated with patient survival across diverse cancer types. Gain- and loss-of-function experiments demonstrate that tumor STC1 supports tumor progression and enables tumor resistance to checkpoint blockade in murine tumor models. Mechanistically, tumor STC1 interacts with calreticulin (CRT), an "eat-me" signal, and minimizes CRT membrane exposure, thereby abrogating membrane CRT-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells. Consequently, this impairs APC capacity of antigen presentation and T cell activation. Thus, tumor STC1 inhibits APC phagocytosis and contributes to tumor immune evasion and immunotherapy resistance. We suggest that STC1 is a previously unappreciated phagocytosis checkpoint and targeting STC1 and its interaction with CRT may sensitize to cancer immunotherapy.
Topics: Animals; Antigen Presentation; Glycoproteins; Immunotherapy; Lymphocyte Activation; Macrophages; Mice; Phagocytosis; Receptors, Immunologic; Tumor Escape
PubMed: 33513345
DOI: 10.1016/j.ccell.2020.12.023 -
Frontiers in Immunology 2022The C-type lectin receptor Dectin-1 was originally described as the β-glucan receptor expressed in myeloid cells, with crucial functions in antifungal responses.... (Review)
Review
The C-type lectin receptor Dectin-1 was originally described as the β-glucan receptor expressed in myeloid cells, with crucial functions in antifungal responses. However, over time, different ligands both of microbial-derived and endogenous origin have been shown to be recognized by Dectin-1. The outcomes of this recognition are diverse, including pro-inflammatory responses such as cytokine production, reactive oxygen species generation and phagocytosis. Nonetheless, tolerant responses have been also attributed to Dectin-1, depending on the specific ligand engaged. Dectin-1 recognition of their ligands triggers a plethora of downstream signaling pathways, with complex interrelationships. These signaling routes can be modulated by diverse factors such as phosphatases or tetraspanins, resulting either in pro-inflammatory or regulatory responses. Since its first depiction, Dectin-1 has recently gained a renewed attention due to its role in the induction of trained immunity. This process of long-term memory of innate immune cells can be triggered by β-glucans, and Dectin-1 is crucial for its initiation. The main signaling pathways involved in this process have been described, although the understanding of the above-mentioned complexity in the β-glucan-induced trained immunity is still scarce. In here, we have reviewed and updated all these factors related to the biology of Dectin-1, highlighting the gaps that deserve further research. We believe on the relevance to fully understand how this receptor works, and therefore, how we could harness it in different pathological conditions as diverse as fungal infections, autoimmunity, or cancer.
Topics: Lectins, C-Type; Ligands; Phagocytosis; Signal Transduction; beta-Glucans
PubMed: 35237264
DOI: 10.3389/fimmu.2022.812148