-
Journal of Molecular Medicine (Berlin,... Jul 2024Atherosclerosis (AS) is a chronic inflammatory vascular disease that occurs in the intima of large and medium-sized arteries with the immune system's involvement. It is... (Review)
Review
Atherosclerosis (AS) is a chronic inflammatory vascular disease that occurs in the intima of large and medium-sized arteries with the immune system's involvement. It is a common pathological basis for high morbidity and mortality of cardiovascular diseases. Abnormal proliferation of apoptotic cells and necrotic cells leads to AS plaque expansion, necrotic core formation, and rupture. In the early stage of AS, macrophages exert an efferocytosis effect to engulf and degrade apoptotic, dead, damaged, or senescent cells by efferocytosis, thus enabling the regulation of the organism. In the early stage of AS, macrophages rely on this effect to slow down the process of AS. However, in the advanced stage of AS, the efferocytosis of macrophages within the plaque is impaired, which leads to the inability of macrophages to promptly remove the apoptotic cells (ACs) from the organism promptly, causing exacerbation of AS. Moreover, upregulation of CD47 expression in AS plaques also protects ACs from phagocytosis by macrophages, resulting in a large amount of residual ACs in the plaque, further expanding the necrotic core. In this review, we discussed the molecular mechanisms involved in the process of efferocytosis and how efferocytosis is impaired and regulated during AS, hoping to provide new insights for treating AS.
Topics: Humans; Atherosclerosis; Animals; Phagocytosis; Macrophages; Apoptosis; Plaque, Atherosclerotic; CD47 Antigen; Necrosis; Efferocytosis
PubMed: 38727748
DOI: 10.1007/s00109-024-02439-3 -
Biology of the Cell Dec 2023Persistent myelin debris can inhibit axonal regeneration, thereby hindering remyelination. Effective removal of myelin debris is essential to eliminate the interference...
BACKGROUND INFORMATION
Persistent myelin debris can inhibit axonal regeneration, thereby hindering remyelination. Effective removal of myelin debris is essential to eliminate the interference of myelin debris in oligodendrocyte progenitor cell (OPC) activation, recruitment to demyelinating sites and/or differentiation into mature oligodendrocytes (OLs). In addition to microglia, it has been reported that astrocytic phagocytosis of myelin debris is a feature of early demyelination.
RESULTS
In the present study, astrocytes effectively phagocytized myelin debris in vitro and in vivo. On the 5th day after injecting myelin debris into the brain, astrocytes were enriched in the area injected with myelin debris compared with microglia, and their ability to engulf myelin debris was stronger than that of microglia. When exposed to myelin debris, astrocytes phagocytizing myelin debris triggered self-apoptosis, accompanied by the activation of NF-κB, down-regulation of Nrf2, and the increase of ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF). However, the activation of astrocytic NF-κB did not influence the inflammatory cytokines IL-1β, IL-6, and TNF-α, and the anti-inflammatory factor IL-10. The proliferation of astrocytes and mobilization of OPCs in the subventricular zone were elevated on the 5th day after intracerebral injection of myelin debris.
CONCLUSIONS
The results suggested that myelin phagocytosis of astrocytes should help improve the microenvironment and promote myelin regeneration by increasing CNTF and bFGF within the central nervous system.
SIGNIFICANCE
However, the molecular interaction of astrocytes acting as phagocytes remains to be further explored. Therefore, an improvement of astrocytes to phagocytize myelin debris may be a promising treatment measure to prevent demyelination and promote remyelination in MS and other diseases with prominent myelin injury.
Topics: Humans; Myelin Sheath; Astrocytes; Demyelinating Diseases; Ciliary Neurotrophic Factor; NF-kappa B; Phagocytosis; Oligodendroglia
PubMed: 37851997
DOI: 10.1111/boc.202300057 -
Frontiers in Immunology 2023Low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1), also known as receptor associated protein (RAP), is an endoplasmic reticulum (ER)...
Low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1), also known as receptor associated protein (RAP), is an endoplasmic reticulum (ER) chaperone and inhibitor of LDL receptor related protein 1 (LRP1) and related receptors. These receptors have dozens of physiological ligands and cell functions, but it is not known whether cells release LRPAP1 physiologically at levels that regulate these receptors and cell functions. We used mouse BV-2 and human CHME3 microglial cell lines, and found that microglia released nanomolar levels of LRPAP1 when inflammatory activated by lipopolysaccharide or when ER stressed by tunicamycin. LRPAP1 was found on the surface of live activated and non-activated microglia, and anti-LRPAP1 antibodies induced internalization. Addition of 10 nM LRPAP1 inhibited microglial phagocytosis of isolated synapses and cells, and the uptake of Aβ. LRPAP1 also inhibited Aβ aggregation . Thus, activated and stressed microglia release LRPAP1 levels that can inhibit phagocytosis, Aβ uptake and Aβ aggregation. We conclude that LRPAP1 release may regulate microglial functions and Aβ pathology, and more generally that extracellular LRPAP1 may be a physiological and pathological regulator of a wide range of cell functions.
Topics: Animals; Humans; Mice; Amyloid beta-Peptides; Carrier Proteins; Cell Line; Cells, Cultured; Microglia; Phagocytosis; LDL-Receptor Related Protein-Associated Protein
PubMed: 38035103
DOI: 10.3389/fimmu.2023.1286474 -
Microbiological Research Dec 2023Many pathogenic organisms need to reach either an intracellular compartment or the cytoplasm of a target cell for their survival, replication or immune system evasion.... (Review)
Review
Many pathogenic organisms need to reach either an intracellular compartment or the cytoplasm of a target cell for their survival, replication or immune system evasion. Intracellular pathogens frequently penetrate into the cell through the endocytic and phagocytic pathways (clathrin-mediated endocytosis, phagocytosis and macropinocytosis) that culminates in fusion with lysosomes. However, several mechanisms are triggered by pathogenic microorganisms - protozoan, bacteria, virus and fungus - to avoid destruction by lysosome fusion, such as rupture of the phagosome and thereby release into the cytoplasm, avoidance of autophagy, delaying in both phagolysosome biogenesis and phagosomal maturation and survival/replication inside the phagolysosome. Here we reviewed the main data dealing with phagosome maturation and evasion from lysosomal killing by different bacteria, protozoa, fungi and virus.
Topics: Lysosomes; Phagocytosis; Phagosomes; Endocytosis; Immune Evasion
PubMed: 37748260
DOI: 10.1016/j.micres.2023.127503 -
Advanced Materials (Deerfield Beach,... May 2024The removal of dying cells, or efferocytosis, is an indispensable part of resolving inflammation. However, the inflammatory microenvironment of the atherosclerotic...
The removal of dying cells, or efferocytosis, is an indispensable part of resolving inflammation. However, the inflammatory microenvironment of the atherosclerotic plaque frequently affects the biology of both apoptotic cells and resident phagocytes, rendering efferocytosis dysfunctional. To overcome this problem, a chimeric antigen receptor (CAR) macrophage that can target and engulf phagocytosis-resistant apoptotic cells expressing CD47 is developed. In both normal and inflammatory circumstances, CAR macrophages exhibit activity equivalent to antibody blockage. The surface of CAR macrophages is modified with reactive oxygen species (ROS)-responsive therapeutic nanoparticles targeting the liver X receptor pathway to improve their cell effector activities. The combination of CAR and nanoparticle engineering activated lipid efflux pumps enhances cell debris clearance and reduces inflammation. It is further suggested that the undifferentiated CAR-Ms can transmigrate within a mico-fabricated vessel system. It is also shown that our CAR macrophage can act as a chimeric switch receptor (CSR) to withstand the immunosuppressive inflammatory environment. The developed platform has the potential to contribute to the advancement of next-generation cardiovascular disease therapies and further studies include in vivo experiments.
Topics: Nanoparticles; Macrophages; Liver X Receptors; Animals; Receptors, Chimeric Antigen; Phagocytosis; Mice; Humans; Signal Transduction; Reactive Oxygen Species; CD47 Antigen; Apoptosis; Efferocytosis; Liposomes
PubMed: 38353580
DOI: 10.1002/adma.202308377 -
Translational Neurodegeneration Oct 2023Microglia, the resident immune cells of the brain, are increasingly implicated in the regulation of brain health and disease. Microglia perform multiple functions in the... (Review)
Review
Microglia, the resident immune cells of the brain, are increasingly implicated in the regulation of brain health and disease. Microglia perform multiple functions in the central nervous system, including surveillance, phagocytosis and release of a variety of soluble factors. Importantly, a majority of their functions are closely related to changes in their metabolism. This natural inter-dependency between core microglial properties and metabolism offers a unique opportunity to modulate microglial activities via nutritional or metabolic interventions. In this review, we examine the existing scientific literature to synthesize the hypothesis that microglial phagocytosis of amyloid beta (Aβ) aggregates in Alzheimer's disease (AD) can be selectively enhanced via metabolic interventions. We first review the basics of microglial metabolism and the effects of common metabolites, such as glucose, lipids, ketone bodies, glutamine, pyruvate and lactate, on microglial inflammatory and phagocytic properties. Next, we examine the evidence for dysregulation of microglial metabolism in AD. This is followed by a review of in vivo studies on metabolic manipulation of microglial functions to ascertain their therapeutic potential in AD. Finally, we discuss the effects of metabolic factors on microglial phagocytosis of healthy synapses, a pathological process that also contributes to the progression of AD. We conclude by enlisting the current challenges that need to be addressed before strategies to harness microglial phagocytosis to clear pathological protein deposits in AD and other neurodegenerative disorders can be widely adopted.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Microglia; Phagocytosis; Brain
PubMed: 37908010
DOI: 10.1186/s40035-023-00382-w -
Current Opinion in Neurobiology Jun 2024Microglia are tissue-resident macrophages and professional phagocytes of the central nervous system (CNS). In development, microglia-mediated phagocytosis is important... (Review)
Review
Microglia are tissue-resident macrophages and professional phagocytes of the central nervous system (CNS). In development, microglia-mediated phagocytosis is important for sculpting the cellular architecture. This includes the engulfment of dead/dying cells, pruning extranumerary synapses and axons, and phagocytosing fragments of myelin sheaths. Intriguingly, these developmental phagocytic mechanisms by which microglia sculpt the CNS are now appreciated as important for eliminating synapses, myelin, and proteins during neurodegeneration. Here, we discuss parallels between neurodevelopment and neurodegeneration, which highlights how development is informing disease. We further discuss recent advances and challenges towards therapeutically targeting these phagocytic pathways and how we can leverage development to overcome these challenges.
Topics: Humans; Microglia; Animals; Phagocytosis; Neurodegenerative Diseases; Myelin Sheath; Central Nervous System
PubMed: 38631077
DOI: 10.1016/j.conb.2024.102877 -
Immunological Reviews Oct 2023The failure to resolve inflammation underpins to several prevalent diseases, like atherosclerosis, and so identifying ways to boost resolution is unmet clinical needs.... (Review)
Review
The failure to resolve inflammation underpins to several prevalent diseases, like atherosclerosis, and so identifying ways to boost resolution is unmet clinical needs. The resolution of inflammation is governed by several factors such as specialized pro-resolving mediators (SPMs) that counter-regulate pro-inflammatory pathways and promote tissue repair without compromising host defense. A major function of nearly all SPMs is to enhance the clearance of dead cells or efferocytosis. As such, phagocytes, such as macrophages, are essential cellular players in the resolution of inflammation because of their ability to rapidly and efficiently clear dead cells. This review highlights the role of SPMs in the clearance of apoptotic and necroptotic cells and offers insights into how targeting efferocytosis may provide new treatments for non-resolving diseases, like atherosclerosis.
Topics: Humans; Inflammation; Phagocytosis; Atherosclerosis; Macrophages; Inflammation Mediators
PubMed: 37787174
DOI: 10.1111/imr.13278 -
Archives of Microbiology Mar 2024Respiratory viruses have caused severe global health problems and posed essential challenges to the medical community. In recent years, the role of autophagy as a... (Review)
Review
Respiratory viruses have caused severe global health problems and posed essential challenges to the medical community. In recent years, the role of autophagy as a critical process in cells in viral respiratory diseases has been noticed. One of the vital catabolic biological processes in the body is autophagy. Autophagy contributes to energy recovery by targeting and selectively directing foreign microorganisms, organelles, and senescent intracellular proteins to the lysosome for degradation and phagocytosis. Activation or suppression of autophagy is often initiated when foreign pathogenic organisms such as viruses infect cells. Because of its antiviral properties, several viruses may escape or resist this process by encoding viral proteins. Viruses can also use autophagy to enhance their replication or prolong the persistence of latent infections. Here, we provide an overview of autophagy and respiratory viruses such as coronavirus, rhinovirus, parainfluenza, influenza, adenovirus, and respiratory syncytial virus, and examine the interactions between them and the role of autophagy in the virus-host interaction process and the resulting virus replication strategy.
Topics: Humans; Autophagy; Phagocytosis; Adenoviridae; Influenza, Human; Coronavirus Infections
PubMed: 38436746
DOI: 10.1007/s00203-024-03838-3 -
The Journal of Cell Biology Nov 2023Src family kinases (SFKs) are evolutionarily conserved proteins acting downstream of receptors and regulating cellular processes including proliferation, adhesion, and...
Src family kinases (SFKs) are evolutionarily conserved proteins acting downstream of receptors and regulating cellular processes including proliferation, adhesion, and migration. Elevated SFK expression and activity correlate with progression of a variety of cancers. Here, using the Drosophila melanogaster border cells as a model, we report that localized activation of a Src kinase promotes an unusual behavior: engulfment of one cell by another. By modulating Src expression and activity in the border cell cluster, we found that increased Src kinase activity, either by mutation or loss of a negative regulator, is sufficient to drive one cell to engulf another living cell. We elucidate a molecular mechanism that requires integrins, the kinases SHARK and FAK, and Rho family GTPases, but not the engulfment receptor Draper. We propose that cell cannibalism is a result of aberrant phagocytosis, where cells with dysregulated Src activity fail to differentiate between living and dead or self versus non-self, thus driving this malignant behavior.
Topics: Animals; Cytophagocytosis; Drosophila melanogaster; src-Family Kinases
PubMed: 37747450
DOI: 10.1083/jcb.202302076