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1.
Annu Rev Immunol ; 36: 489-517, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29400998

RESUMO

The human body generates 10-100 billion cells every day, and the same number of cells die to maintain homeostasis in our body. Cells infected by bacteria or viruses also die. The cell death that occurs under physiological conditions mainly proceeds by apoptosis, which is a noninflammatory, or silent, process, while pathogen infection induces necroptosis or pyroptosis, which activates the immune system and causes inflammation. Dead cells generated by apoptosis are quickly engulfed by macrophages for degradation. Caspases are a large family of cysteine proteases that act in cascades. A cascade that leads to caspase 3 activation mediates apoptosis and is responsible for killing cells, recruiting macrophages, and presenting an "eat me" signal(s). When apoptotic cells are not efficiently engulfed by macrophages, they undergo secondary necrosis and release intracellular materials that represent a damage-associated molecular pattern, which may lead to a systemic lupus-like autoimmune disease.


Assuntos
Apoptose/imunologia , Fagocitose/imunologia , Animais , Biomarcadores , Caspases/metabolismo , Morte Celular , Humanos , Lisossomos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Fosfatidilserinas/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Receptores de Morte Celular/metabolismo , Transdução de Sinais , Especificidade por Substrato
2.
Annu Rev Immunol ; 36: 717-753, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29490164

RESUMO

Antigen cross-presentation is an adaptation of the cellular process of loading MHC-I molecules with endogenous peptides during their biosynthesis within the endoplasmic reticulum. Cross-presented peptides derive from internalized proteins, microbial pathogens, and transformed or dying cells. The physical separation of internalized cargo from the endoplasmic reticulum, where the machinery for assembling peptide-MHC-I complexes resides, poses a challenge. To solve this problem, deliberate rewiring of organelle communication within cells is necessary to prepare for cross-presentation, and different endocytic receptors and vesicular traffic patterns customize the emergent cross-presentation compartment to the nature of the peptide source. Three distinct pathways of vesicular traffic converge to form the ideal cross-presentation compartment, each regulated differently to supply a unique component that enables cross-presentation of a diverse repertoire of peptides. Delivery of centerpiece MHC-I molecules is the critical step regulated by microbe-sensitive Toll-like receptors. Defining the subcellular sources of MHC-I and identifying sites of peptide loading during cross-presentation remain key challenges.


Assuntos
Apresentação de Antígeno/imunologia , Antígenos/imunologia , Apresentação Cruzada/imunologia , Imunomodulação , Animais , Transporte Biológico , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Endocitose/imunologia , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Epitopos/imunologia , Epitopos/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Espaço Intracelular/metabolismo , Fagocitose/imunologia , Proteólise , Receptores de Superfície Celular/metabolismo
3.
Annu Rev Immunol ; 35: 149-176, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28125356

RESUMO

To monitor the health of cells, the immune system tasks antigen-presenting cells with gathering antigens from other cells and bringing them to CD8 T cells in the form of peptides bound to MHC-I molecules. Most cells would be unable to perform this function because they use their MHC-I molecules to exclusively present peptides derived from the cell's own proteins. However, the immune system evolved mechanisms for dendritic cells and some other phagocytes to sample and present antigens from the extracellular milieu on MHC-I through a process called cross-presentation. How this important task is accomplished, its role in health and disease, and its potential for exploitation are the subject of this review.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada , Células Dendríticas/imunologia , Animais , Antígenos/imunologia , Antígenos/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Vigilância Imunológica , Ativação Linfocitária , Fagocitose
4.
Cell ; 185(22): 4135-4152.e22, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36257314

RESUMO

Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aß) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aß deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer's disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3ß-signaling, and restrict Aß phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aß load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Animais , Camundongos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Camundongos Transgênicos , Microglia/patologia , Fagocitose
5.
Cell ; 185(26): 4887-4903.e17, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36563662

RESUMO

Our bodies turn over billions of cells daily via apoptosis and are in turn cleared by phagocytes via the process of "efferocytosis." Defects in efferocytosis are now linked to various inflammatory diseases. Here, we designed a strategy to boost efferocytosis, denoted "chimeric receptor for efferocytosis" (CHEF). We fused a specific signaling domain within the cytoplasmic adapter protein ELMO1 to the extracellular phosphatidylserine recognition domains of the efferocytic receptors BAI1 or TIM4, generating BELMO and TELMO, respectively. CHEF-expressing phagocytes display a striking increase in efferocytosis. In mouse models of inflammation, BELMO expression attenuates colitis, hepatotoxicity, and nephrotoxicity. In mechanistic studies, BELMO increases ER-resident enzymes and chaperones to overcome protein-folding-associated toxicity, which was further validated in a model of ER-stress-induced renal ischemia-reperfusion injury. Finally, TELMO introduction after onset of kidney injury significantly reduced fibrosis. Collectively, these data advance a concept of chimeric efferocytic receptors to boost efferocytosis and dampen inflammation.


Assuntos
Macrófagos , Fagocitose , Animais , Camundongos , Macrófagos/metabolismo , Inflamação/metabolismo , Fagócitos/metabolismo , Proteínas de Transporte/metabolismo , Apoptose , Proteínas Adaptadoras de Transdução de Sinal/metabolismo
6.
Nat Immunol ; 25(4): 622-632, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38454157

RESUMO

The development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a phenylalanine-to-serine mutation at position 375 (F375S) in the spike protein of Omicron to revert it to the sequence found in Delta and other ancestral strains significantly enhanced the immunogenicity of Omicron vaccines. Sequence FAPFFAF at position 371-377 in Omicron spike had a potent inhibitory effect on macrophage uptake of receptor-binding domain (RBD) nanoparticles or spike-pseudovirus particles containing this sequence. Omicron RBD enhanced binding to Siglec-9 on macrophages to impair phagocytosis and antigen presentation and promote immune evasion, which could be abrogated by the F375S mutation. A bivalent F375S Omicron RBD and Delta-RBD nanoparticle vaccine elicited potent and broad nAbs in mice, rabbits and rhesus macaques. Our research suggested that manipulation of the Siglec-9 pathway could be a promising approach to enhance vaccine response.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Camundongos , Coelhos , Anticorpos Neutralizantes , Anticorpos Antivirais , Macaca mulatta , Macrófagos , Nanovacinas , Fagocitose , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico
7.
Annu Rev Immunol ; 32: 25-50, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24215318

RESUMO

CD47 is a broadly expressed membrane protein that interacts with the myeloid inhibitory immunoreceptor SIRPα (also termed CD172a or SHPS-1). SIRPα is the prototypic member of the SIRP paired receptor family of closely related SIRP proteins. Engagement of SIRPα by CD47 provides a downregulatory signal that inhibits host cell phagocytosis, and CD47 therefore functions as a "don't-eat-me" signal. Here, we discuss recent structural analysis of CD47-SIRPα interactions and implications of this for the function and evolution of SIRPα and paired receptors in general. Furthermore, we review the proposed roles of CD47-SIRPα interactions in phagocytosis, (auto)immunity, and host defense, as well as its potential significance as a therapeutic target in cancer and inflammation and for improving graft survival in xenotransplantation.


Assuntos
Antígenos de Diferenciação/metabolismo , Antígeno CD47/metabolismo , Receptores Imunológicos/metabolismo , Animais , Antígenos de Diferenciação/química , Antígenos de Diferenciação/genética , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/etiologia , Antígeno CD47/química , Antígeno CD47/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Doenças Hematológicas/tratamento farmacológico , Doenças Hematológicas/etiologia , Humanos , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/metabolismo , Terapia de Alvo Molecular , Família Multigênica , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Ligação Proteica/efeitos dos fármacos , Receptores Imunológicos/química , Receptores Imunológicos/genética , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo
8.
Cell ; 184(4): 969-982.e13, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33571427

RESUMO

Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%-5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in one-third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron levels in African Americans.


Assuntos
Canais Iônicos/metabolismo , Ferro/metabolismo , Negro ou Afro-Americano , Envelhecimento/metabolismo , Alelos , Animais , Estudos de Coortes , Contagem de Eritrócitos , Eritropoese , Mutação com Ganho de Função/genética , Hepatócitos/metabolismo , Hepcidinas/sangue , Hepcidinas/metabolismo , Humanos , Ferro/sangue , Sobrecarga de Ferro/metabolismo , Macrófagos/metabolismo , Mecanotransdução Celular , Camundongos Endogâmicos C57BL , Fagocitose , Fenótipo , Estresse Fisiológico
9.
Cell ; 184(17): 4480-4494.e15, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34320407

RESUMO

In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells.


Assuntos
Fagocitose , Fosfofrutoquinase-1 Hepática/metabolismo , Explosão Respiratória , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Regulação Alostérica/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinética , Viabilidade Microbiana/efeitos dos fármacos , Modelos Moleculares , NADPH Oxidases/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fagocitose/efeitos dos fármacos , Proteínas de Ligação a Fosfato/metabolismo , Fosfofrutoquinase-1 Hepática/antagonistas & inibidores , Fosfofrutoquinase-1 Hepática/ultraestrutura , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Recombinantes/isolamento & purificação , Explosão Respiratória/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia
10.
Nat Immunol ; 24(11): 1813-1824, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37813965

RESUMO

Kupffer cells, the liver tissue resident macrophages, are critical in the detection and clearance of cancer cells. However, the molecular mechanisms underlying their detection and phagocytosis of cancer cells are still unclear. Using in vivo genome-wide CRISPR-Cas9 knockout screening, we found that the cell-surface transmembrane protein ERMAP expressed on various cancer cells signaled to activate phagocytosis in Kupffer cells and to control of liver metastasis. ERMAP interacted with ß-galactoside binding lectin galectin-9 expressed on the surface of Kupffer cells in a manner dependent on glycosylation. Galectin-9 formed a bridging complex with ERMAP and the transmembrane receptor dectin-2, expressed on Kupffer cells, to induce the detection and phagocytosis of cancer cells by Kupffer cells. Patients with low expression of ERMAP on tumors had more liver metastases. Thus, our study identified the ERMAP-galectin-9-dectin-2 axis as an 'eat me' signal for Kupffer cells.


Assuntos
Citofagocitose , Células de Kupffer , Humanos , Fagocitose/genética , Galectinas/genética , Galectinas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
11.
Nat Immunol ; 24(12): 2032-2041, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37945822

RESUMO

Cancer cells often overexpress CD47, which triggers the inhibitory receptor SIRPα expressed on macrophages, to elude phagocytosis and antitumor immunity. Pharmacological blockade of CD47 or SIRPα is showing promise as anticancer therapy, although CD47 blockade has been associated with hematological toxicities that may reflect its broad expression pattern on normal cells. Here we found that, in addition to triggering SIRPα, CD47 suppressed phagocytosis by a SIRPα-independent mechanism. This mechanism prevented phagocytosis initiated by the pro-phagocytic ligand, SLAMF7, on tumor cells, due to a cis interaction between CD47 and SLAMF7. The CD47-SLAMF7 interaction was disrupted by CD47 blockade and by a first-in-class agonist SLAMF7 antibody, but not by SIRPα blockade, thereby promoting antitumor immunity. Hence, CD47 suppresses phagocytosis not only by engaging SIRPα, but also by masking cell-intrinsic pro-phagocytic ligands on tumor cells and knowledge of this mechanism may influence the decision between CD47 blockade or SIRPα blockade for therapeutic purposes.


Assuntos
Antígeno CD47 , Neoplasias , Evasão Tumoral , Humanos , Antígenos de Diferenciação/metabolismo , Antígenos de Diferenciação/uso terapêutico , Ligantes , Macrófagos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Fagocitose , Animais , Camundongos
12.
Annu Rev Immunol ; 31: 675-704, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23330955

RESUMO

Phosphoinositide 3-kinases (PI3Ks) control many important aspects of immune cell development, differentiation, and function. Mammals have eight PI3K catalytic subunits that are divided into three classes based on similarities in structure and function. Specific roles for the class I PI3Ks have been broadly investigated and are relatively well understood, as is the function of their corresponding phosphatases. More recently, specific roles for the class II and class III PI3Ks have emerged. Through vertebrate evolution and in parallel with the evolution of adaptive immunity, there has been a dramatic increase not only in the genes for PI3K subunits but also in genes for phosphatases that act on 3-phosphoinositides and in 3-phosphoinositide-binding proteins. Our understanding of the PI3Ks in immunity is guided by fundamental discoveries made in simpler model organisms as well as by appreciating new adaptations of this signaling module in mammals in general and in immune cells in particular.


Assuntos
Família Multigênica/imunologia , Fosfatidilinositol 3-Quinases/fisiologia , Transdução de Sinais/imunologia , Animais , Domínio Catalítico/imunologia , Endocitose/imunologia , Humanos , Complexos Multiproteicos/imunologia , Fagocitose/imunologia , Fosfatidilinositol 3-Quinases/classificação , Transporte Proteico/imunologia
13.
Cell ; 183(1): 110-125.e11, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32888431

RESUMO

During respiration, humans breathe in more than 10,000 liters of non-sterile air daily, allowing some pathogens access to alveoli. Interestingly, alveoli outnumber alveolar macrophages (AMs), which favors alveoli devoid of AMs. If AMs, like most tissue macrophages, are sessile, then this numerical advantage would be exploited by pathogens unless neutrophils from the blood stream intervened. However, this would translate to omnipresent persistent inflammation. Developing in vivo real-time intravital imaging of alveoli revealed AMs crawling in and between alveoli using the pores of Kohn. Importantly, these macrophages sensed, chemotaxed, and, with high efficiency, phagocytosed inhaled bacterial pathogens such as P. aeruginosa and S. aureus, cloaking the bacteria from neutrophils. Impairing AM chemotaxis toward bacteria induced superfluous neutrophil recruitment, leading to inappropriate inflammation and injury. In a disease context, influenza A virus infection impaired AM crawling via the type II interferon signaling pathway, and this greatly increased secondary bacterial co-infection.


Assuntos
Bactérias/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Animais , Feminino , Homeostase , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Neutrófilos/imunologia , Fagocitose/imunologia , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/patogenicidade , Alvéolos Pulmonares , Transdução de Sinais , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade
14.
Cell ; 183(1): 94-109.e23, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937105

RESUMO

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. VIDEO ABSTRACT.


Assuntos
Macrófagos/metabolismo , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Idoso , Animais , Apoptose , Autofagia , Feminino , Coração/fisiologia , Homeostase , Humanos , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/fisiologia , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/fisiologia , Fagocitose/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , c-Mer Tirosina Quinase/metabolismo
15.
Cell ; 183(7): 1867-1883.e26, 2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33248023

RESUMO

Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.


Assuntos
Atresia Biliar/imunologia , Atresia Biliar/terapia , Fígado/imunologia , Animais , Antígenos CD20/metabolismo , Linfócitos B/imunologia , Atresia Biliar/sangue , Atresia Biliar/tratamento farmacológico , Biópsia , Receptor 1 de Quimiocina CX3C/metabolismo , Morte Celular , Linhagem Celular , Proliferação de Células , Transdiferenciação Celular , Criança , Pré-Escolar , Estudos de Coortes , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina G/metabolismo , Lactente , Inflamação/patologia , Células Matadoras Naturais/imunologia , Células de Kupffer/patologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Depleção Linfocítica , Linfopoese , Masculino , Camundongos Endogâmicos BALB C , Fagocitose , RNA/metabolismo , Rituximab/administração & dosagem , Rituximab/farmacologia , Rituximab/uso terapêutico , Rotavirus/fisiologia , Análise de Célula Única , Células Th1/imunologia , Células Th17/imunologia
16.
Annu Rev Cell Dev Biol ; 37: 89-114, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34152790

RESUMO

Recent observations indicate that, rather than being an all-or-none response, phagocytosis is finely tuned by a host of developmental and environmental factors. The expression of key phagocytic determinants is regulated via transcriptional and epigenetic means that confer memory on the process. Membrane traffic, the cytoskeleton, and inside-out signaling control the activation of phagocytic receptors and their ability to access their targets. An exquisite extra layer of complexity is introduced by the coexistence of distinct "eat-me" and "don't-eat-me" signals on targets and of corresponding "eat" and "don't-eat" receptors on the phagocyte surface. Moreover, assorted physical barriers constitute "don't-come-close-to-me" hurdles that obstruct the engagement of ligands by receptors. The expression, mobility, and accessibility of all these determinants can be modulated, conferring extreme plasticity on phagocytosis and providing attractive targets for therapeutic intervention in cancer, atherosclerosis, and dementia.


Assuntos
Neoplasias , Plásticos , Humanos , Fagócitos , Fagocitose/genética , Plásticos/uso terapêutico , Transdução de Sinais/fisiologia
17.
Nat Immunol ; 23(8): 1148-1156, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35879449

RESUMO

Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being re-discovered as regulators of several diseases, including cancer. Tumor-associated macrophages (TAMs) represent the most abundant innate immune population in the tumor microenvironment (TME). Macrophages are professional phagocytic cells of the hematopoietic system specializing in the detection, phagocytosis and destruction of bacteria and other harmful micro-organisms, apoptotic cells and metabolic byproducts. In contrast to these healthy macrophage functions, TAMs support cancer cell growth and metastasis and mediate immunosuppressive effects on the adaptive immune cells of the TME. Cancer is one of the most potent insults on macrophage physiology, inducing changes that are intimately linked with disease progression. In this Review, we outline hallmarks of TAMs and discuss the emerging mechanisms that contribute to their pathophysiological adaptations and the vulnerabilities that provide attractive targets for therapeutic exploitation in cancer.


Assuntos
Neoplasias , Microambiente Tumoral , Progressão da Doença , Humanos , Macrófagos , Fagocitose
18.
Nat Immunol ; 23(2): 229-236, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34949832

RESUMO

Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.


Assuntos
Relógios Circadianos/genética , Macrófagos/fisiologia , Envelhecimento , Animais , Aterosclerose/genética , Diferenciação Celular/genética , Regulação da Expressão Gênica/genética , Imunidade Inata/genética , Inflamação/genética , Fator 4 Semelhante a Kruppel/genética , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Fagocitose/genética
19.
Cell ; 179(1): 51-53, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31539498

RESUMO

In this issue of Cell, Zhu et al. show that in the developing zebrafish, neural crest cells can act as professional phagocytes and directionally approach apoptotic cells to clear the larval nervous system from cell debris.


Assuntos
Crista Neural , Proteínas de Peixe-Zebra , Animais , Sistema Nervoso , Fagocitose , Peixe-Zebra
20.
Cell ; 179(1): 74-89.e10, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31495570

RESUMO

During neural tube closure and spinal cord development, many cells die in both the central and peripheral nervous systems (CNS and PNS, respectively). However, myeloid-derived professional phagocytes have not yet colonized the trunk region during early neurogenesis. How apoptotic cells are removed from this region during these stages remains largely unknown. Using live imaging in zebrafish, we demonstrate that neural crest cells (NCCs) respond rapidly to dying cells and phagocytose cellular debris around the neural tube. Additionally, NCCs have the ability to enter the CNS through motor exit point transition zones and clear debris in the spinal cord. Surprisingly, NCCs phagocytosis mechanistically resembles macrophage phagocytosis and their recruitment toward cellular debris is mediated by interleukin-1ß. Taken together, our results reveal a role for NCCs in phagocytosis of debris in the developing nervous system before the presence of professional phagocytes.


Assuntos
Movimento Celular/fisiologia , Crista Neural/fisiologia , Neurogênese/fisiologia , Sistema Nervoso Periférico/crescimento & desenvolvimento , Fagocitose/fisiologia , Medula Espinal/crescimento & desenvolvimento , Animais , Animais Geneticamente Modificados , Apoptose/fisiologia , Diferenciação Celular/fisiologia , Interleucina-1beta/metabolismo , Fagócitos/fisiologia , Fagossomos/fisiologia , Peixe-Zebra/embriologia
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