RESUMO
Microbial communities are resident to multiple niches of the human body and are important modulators of the host immune system and responses to anticancer therapies. Recent studies have shown that complex microbial communities are present within primary tumors. To investigate the presence and relevance of the microbiome in metastases, we integrated mapping and assembly-based metagenomics, genomics, transcriptomics, and clinical data of 4,160 metastatic tumor biopsies. We identified organ-specific tropisms of microbes, enrichments of anaerobic bacteria in hypoxic tumors, associations between microbial diversity and tumor-infiltrating neutrophils, and the association of Fusobacterium with resistance to immune checkpoint blockade (ICB) in lung cancer. Furthermore, longitudinal tumor sampling revealed temporal evolution of the microbial communities and identified bacteria depleted upon ICB. Together, we generated a pan-cancer resource of the metastatic tumor microbiome that may contribute to advancing treatment strategies.
Assuntos
Microbiota , Metástase Neoplásica , Neoplasias , Humanos , Neoplasias/microbiologia , Neoplasias/patologia , Metagenômica/métodos , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Neutrófilos/imunologia , Microambiente Tumoral , Bactérias/genética , Bactérias/classificaçãoRESUMO
Human autoimmunity against elements conferring protective immunity can be symbolized by the 'ouroboros', a snake eating its own tail. Underlying infection is autoimmunity against three immunological targets: neutrophils, complement and cytokines. Autoantibodies against neutrophils can cause peripheral neutropenia underlying mild pyogenic bacterial infections. The pathogenic contribution of autoantibodies against molecules of the complement system is often unclear, but autoantibodies specific for C3 convertase can enhance its activity, lowering complement levels and underlying severe bacterial infections. Autoantibodies neutralizing granulocyte-macrophage colony-stimulating factor impair alveolar macrophages, thereby underlying pulmonary proteinosis and airborne infections, type I interferon viral diseases, type II interferon intra-macrophagic infections, interleukin-6 pyogenic bacterial diseases and interleukin-17A/F mucocutaneous candidiasis. Each of these five cytokine autoantibodies underlies a specific range of infectious diseases, phenocopying infections that occur in patients with the corresponding inborn errors. In this Review, we analyze this ouroboros of immunity against immunity and posit that it should be considered as a factor in patients with unexplained infection.
Assuntos
Autoanticorpos , Autoimunidade , Humanos , Autoanticorpos/imunologia , Animais , Citocinas/metabolismo , Citocinas/imunologia , Neutrófilos/imunologia , Proteínas do Sistema Complemento/imunologia , Doenças Autoimunes/imunologiaRESUMO
Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.
Assuntos
Fator Ativador de Células B , Interleucina-1beta , Mieloma Múltiplo , Neutrófilos , Células Estromais , Microambiente Tumoral , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Humanos , Microambiente Tumoral/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Células Estromais/metabolismo , Células Estromais/imunologia , Fator Ativador de Células B/metabolismo , Interleucina-1beta/metabolismo , Ativação de Neutrófilo , Fator de Transcrição STAT3/metabolismo , Medula Óssea/imunologia , Medula Óssea/patologiaRESUMO
The adult central nervous system (CNS) possesses a limited capacity for self-repair. Severed CNS axons typically fail to regrow. There is an unmet need for treatments designed to enhance neuronal viability, facilitate axon regeneration and ultimately restore lost neurological functions to individuals affected by traumatic CNS injury, multiple sclerosis, stroke and other neurological disorders. Here we demonstrate that both mouse and human bone marrow neutrophils, when polarized with a combination of recombinant interleukin-4 (IL-4) and granulocyte colony-stimulating factor (G-CSF), upregulate alternative activation markers and produce an array of growth factors, thereby gaining the capacity to promote neurite outgrowth. Moreover, adoptive transfer of IL-4/G-CSF-polarized bone marrow neutrophils into experimental models of CNS injury triggered substantial axon regeneration within the optic nerve and spinal cord. These findings have far-reaching implications for the future development of autologous myeloid cell-based therapies that may bring us closer to effective solutions for reversing CNS damage.
Assuntos
Axônios , Fator Estimulador de Colônias de Granulócitos , Interleucina-4 , Camundongos Endogâmicos C57BL , Regeneração Nervosa , Neutrófilos , Animais , Neutrófilos/imunologia , Regeneração Nervosa/imunologia , Camundongos , Humanos , Axônios/metabolismo , Axônios/fisiologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Interleucina-4/metabolismo , Ativação de Neutrófilo , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/metabolismo , Transferência Adotiva , Citocinas/metabolismo , Células CultivadasRESUMO
Inflammatory pain results from the heightened sensitivity and reduced threshold of nociceptor sensory neurons due to exposure to inflammatory mediators. However, the cellular and transcriptional diversity of immune cell and sensory neuron types makes it challenging to decipher the immune mechanisms underlying pain. Here we used single-cell transcriptomics to determine the immune gene signatures associated with pain development in three skin inflammatory pain models in mice: zymosan injection, skin incision and ultraviolet burn. We found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development and identified cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels and metabolites to generate injury-specific neuroimmune interactomes, we also uncovered that thrombospondin-1 upregulated by immune cells upon injury inhibited nociceptor sensitization. This study lays the groundwork for identifying the neuroimmune axes that modulate pain in diverse disease contexts.
Assuntos
Nociceptores , Dor , Animais , Camundongos , Dor/imunologia , Dor/metabolismo , Nociceptores/metabolismo , Transcriptoma , Camundongos Endogâmicos C57BL , Inflamação/imunologia , Masculino , Macrófagos/imunologia , Macrófagos/metabolismo , Modelos Animais de Doenças , Trombospondina 1/metabolismo , Trombospondina 1/genética , Pele/imunologia , Pele/metabolismo , Pele/patologia , Zimosan , Análise de Célula Única , Neuroimunomodulação , Perfilação da Expressão Gênica , Neutrófilos/imunologia , Neutrófilos/metabolismoRESUMO
Chronic obstructive pulmonary disease (COPD) is a progressive condition of chronic bronchitis, small airway obstruction, and emphysema that represents a leading cause of death worldwide. While inflammation, fibrosis, mucus hypersecretion, and metaplastic epithelial lesions are hallmarks of this disease, their origins and dependent relationships remain unclear. Here we apply single-cell cloning technologies to lung tissue of patients with and without COPD. Unlike control lungs, which were dominated by normal distal airway progenitor cells, COPD lungs were inundated by three variant progenitors epigenetically committed to distinct metaplastic lesions. When transplanted to immunodeficient mice, these variant clones induced pathology akin to the mucous and squamous metaplasia, neutrophilic inflammation, and fibrosis seen in COPD. Remarkably, similar variants pre-exist as minor constituents of control and fetal lung and conceivably act in normal processes of immune surveillance. However, these same variants likely catalyze the pathologic and progressive features of COPD when expanded to high numbers.
Assuntos
Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Adulto , Idoso , Animais , Feminino , Fibrose/fisiopatologia , Humanos , Inflamação/patologia , Pulmão/metabolismo , Masculino , Metaplasia/fisiopatologia , Camundongos , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Análise de Célula Única/métodos , Células-Tronco/metabolismoRESUMO
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/patogenicidadeRESUMO
Systemic immune cell dynamics during coronavirus disease 2019 (COVID-19) are extensively documented, but these are less well studied in the (upper) respiratory tract, where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates1-6. Here, we characterized nasal and systemic immune cells in individuals with COVID-19 who were hospitalized or convalescent and compared the immune cells to those seen in healthy donors. We observed increased nasal granulocytes, monocytes, CD11c+ natural killer (NK) cells and CD4+ T effector cells during acute COVID-19. The mucosal proinflammatory populations positively associated with peripheral blood human leukocyte antigen (HLA)-DRlow monocytes, CD38+PD1+CD4+ T effector (Teff) cells and plasmablasts. However, there was no general lymphopenia in nasal mucosa, unlike in peripheral blood. Moreover, nasal neutrophils negatively associated with oxygen saturation levels in blood. Following convalescence, nasal immune cells mostly normalized, except for CD127+ granulocytes and CD38+CD8+ tissue-resident memory T cells (TRM). SARS-CoV-2-specific CD8+ T cells persisted at least 2 months after viral clearance in the nasal mucosa, indicating that COVID-19 has both transient and long-term effects on upper respiratory tract immune responses.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Nasofaringe/imunologia , Nariz/citologia , Mucosa Respiratória/imunologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , COVID-19/imunologia , COVID-19/patologia , Granulócitos/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Células T de Memória/imunologia , Monócitos/imunologia , Nasofaringe/citologia , Nasofaringe/virologia , Neutrófilos/imunologia , Nariz/imunologia , Nariz/virologia , Estudos Prospectivos , Mucosa Respiratória/citologia , Mucosa Respiratória/virologiaRESUMO
Neutrophils are the most abundant white blood cells in circulation, and patients with congenital neutrophil deficiencies suffer from severe infections that are often fatal, underscoring the importance of these cells in immune defense. In spite of neutrophils' relevance in immunity, research on these cells has been hampered by their experimentally intractable nature. Here, we present a survey of basic neutrophil biology, with an emphasis on examples that highlight the function of neutrophils not only as professional killers, but also as instructors of the immune system in the context of infection and inflammatory disease. We focus on emerging issues in the field of neutrophil biology, address questions in this area that remain unanswered, and critically examine the experimental basis for common assumptions found in neutrophil literature.
Assuntos
Neutrófilos/imunologia , Neutrófilos/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Comunicação Celular/imunologia , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Infecções/imunologia , Infecções/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Ativação de Neutrófilo/imunologiaRESUMO
Neutrophils are attracted to and generate dense swarms at sites of cell damage in diverse tissues, often extending the local disruption of organ architecture produced by the initial insult. Whether the inflammatory damage resulting from such neutrophil accumulation is an inescapable consequence of parenchymal cell death has not been explored. Using a combination of dynamic intravital imaging and confocal multiplex microscopy, we report here that tissue-resident macrophages rapidly sense the death of individual cells and extend membrane processes that sequester the damage, a process that prevents initiation of the feedforward chemoattractant signaling cascade that results in neutrophil swarms. Through this "cloaking" mechanism, the resident macrophages prevent neutrophil-mediated inflammatory damage, maintaining tissue homeostasis in the face of local cell injury that occurs on a regular basis in many organs because of mechanical and other stresses. VIDEO ABSTRACT.
Assuntos
Macrófagos/imunologia , Neutrófilos/imunologia , Alarminas/metabolismo , Animais , Endocitose , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Fibras Musculares Esqueléticas/patologia , Ativação de Neutrófilo , Neutrófilos/metabolismo , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismoRESUMO
Lung cancer is closely associated with chronic inflammation, but the causes of inflammation and the specific immune mediators have not been fully elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here, we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδ T cells. Germ-free or antibiotic-treated mice were significantly protected from lung cancer development induced by Kras mutation and p53 loss. Mechanistically, commensal bacteria stimulated Myd88-dependent IL-1ß and IL-23 production from myeloid cells, inducing proliferation and activation of Vγ6+Vδ1+ γδ T cells that produced IL-17 and other effector molecules to promote inflammation and tumor cell proliferation. Our findings clearly link local microbiota-immune crosstalk to lung tumor development and thereby define key cellular and molecular mediators that may serve as effective targets in lung cancer intervention.
Assuntos
Interações entre Hospedeiro e Microrganismos/imunologia , Linfócitos Intraepiteliais/imunologia , Neoplasias Pulmonares/imunologia , Animais , Proliferação de Células , Feminino , Interleucina-17/imunologia , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Linfócitos Intraepiteliais/metabolismo , Linfócitos Intraepiteliais/fisiologia , Pulmão/imunologia , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Neutrófilos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta , Simbiose/imunologia , Linfócitos T/imunologiaRESUMO
Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.
Assuntos
Resistência à Doença , Neoplasias/patologia , Neutrófilos/imunologia , Sarcoma/patologia , Linfócitos T/metabolismo , Animais , Cromonas/toxicidade , Resistência à Doença/imunologia , Humanos , Imunidade Inata , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Estimativa de Kaplan-Meier , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/mortalidade , Infiltração de Neutrófilos , Neutrófilos/citologia , Neutrófilos/metabolismo , Receptores de Fator Estimulador de Colônias/metabolismo , Sarcoma/induzido quimicamente , Sarcoma/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente TumoralRESUMO
The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-α present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMα to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations.
Assuntos
Ferroptose/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Neutropenia/patologia , Neutrófilos/imunologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Autoanticorpos/imunologia , Autoimunidade/imunologia , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Humanos , Interferon-alfa/imunologia , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Regiões Promotoras Genéticas/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Neutrophils display distinct gene expression patters depending on their developmental stage, activation state and tissue microenvironment. To determine the transcription factor networks that shape these responses in a mouse model, we integrated transcriptional and chromatin analyses of neutrophils during acute inflammation. We showed active chromatin remodeling at two transition stages: bone marrow-to-blood and blood-to-tissue. Analysis of differentially accessible regions revealed distinct sets of putative transcription factors associated with control of neutrophil inflammatory responses. Using ex vivo and in vivo approaches, we confirmed that RUNX1 and KLF6 modulate neutrophil maturation, whereas RELB, IRF5 and JUNB drive neutrophil effector responses and RFX2 and RELB promote survival. Interfering with neutrophil activation by targeting one of these factors, JUNB, reduced pathological inflammation in a mouse model of myocardial infarction. Therefore, our study represents a blueprint for transcriptional control of neutrophil responses in acute inflammation and opens possibilities for stage-specific therapeutic modulation of neutrophil function in disease.
Assuntos
Montagem e Desmontagem da Cromatina/genética , Inflamação/imunologia , Neutrófilos/imunologia , Ativação Transcricional/genética , Animais , Células CHO , Linhagem Celular , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Cricetulus , Feminino , Fatores Reguladores de Interferon/metabolismo , Fator 6 Semelhante a Kruppel/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Fatores de Transcrição de Fator Regulador X/metabolismo , Fator de Transcrição RelB/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica/genéticaRESUMO
Stem cells heal wounds. In this issue of Immunity, Luan et al. demonstrate that epidermal stem cells orchestrate the recruitment of regulatory T (Treg) cells and neutrophils during wound healing. Treg cells facilitate a tolerogenic environment to protect epithelial regeneration while neutrophils promote inflammation to ward off infection.
Assuntos
Neutrófilos , Células-Tronco , Linfócitos T Reguladores , Cicatrização , Cicatrização/imunologia , Humanos , Células-Tronco/imunologia , Linfócitos T Reguladores/imunologia , Animais , Neutrófilos/imunologiaRESUMO
The nervous system, the immune system, and microbial pathogens interact closely at barrier tissues. Here, we find that a bacterial pathogen, Streptococcus pyogenes, hijacks pain and neuronal regulation of the immune response to promote bacterial survival. Necrotizing fasciitis is a life-threatening soft tissue infection in which "pain is out of proportion" to early physical manifestations. We find that S. pyogenes, the leading cause of necrotizing fasciitis, secretes streptolysin S (SLS) to directly activate nociceptor neurons and produce pain during infection. Nociceptors, in turn, release the neuropeptide calcitonin gene-related peptide (CGRP) into infected tissues, which inhibits the recruitment of neutrophils and opsonophagocytic killing of S. pyogenes. Botulinum neurotoxin A and CGRP antagonism block neuron-mediated suppression of host defense, thereby preventing and treating S. pyogenes necrotizing infection. We conclude that targeting the peripheral nervous system and blocking neuro-immune communication is a promising strategy to treat highly invasive bacterial infections. VIDEO ABSTRACT.
Assuntos
Neurônios/metabolismo , Neutrófilos/metabolismo , Infecções Estreptocócicas/patologia , Streptococcus pyogenes/patogenicidade , Animais , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Toxinas Botulínicas Tipo A/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Caspase 1/deficiência , Caspase 1/genética , Diterpenos/farmacologia , Fasciite Necrosante/etiologia , Fasciite Necrosante/patologia , Fasciite Necrosante/veterinária , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neutrófilos/imunologia , Dor/etiologia , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/veterinária , Streptococcus pyogenes/metabolismo , Estreptolisinas/imunologia , Estreptolisinas/metabolismo , Canais de Cátion TRPV/deficiência , Canais de Cátion TRPV/genéticaRESUMO
Skin wounds heal by coordinated induction of inflammation and tissue repair, but the initiating events are poorly defined. Here we uncover a fundamental role of commensal skin microbiota in this process and show that it is mediated by the recruitment and the activation of type I interferon (IFN)-producing plasmacytoid DC (pDC). Commensal bacteria colonizing skin wounds trigger activation of neutrophils to express the chemokine CXCL10, which recruits pDC and acts as an antimicrobial protein to kill exposed microbiota, leading to the formation of CXCL10-bacterial DNA complexes. These complexes and not complexes with host-derived DNA activate pDC to produce type I IFNs, which accelerate wound closure by triggering skin inflammation and early T cell-independent wound repair responses, mediated by macrophages and fibroblasts that produce major growth factors required for healing. These findings identify a key function of commensal microbiota in driving a central innate wound healing response of the skin.
Assuntos
Células Dendríticas/imunologia , Fibroblastos/imunologia , Macrófagos/imunologia , Microbiota/imunologia , Neutrófilos/imunologia , Pele/imunologia , Animais , Células Cultivadas , Quimiocina CXCL10/metabolismo , Humanos , Imunidade Inata , Inflamação , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pele/patologia , Simbiose , CicatrizaçãoRESUMO
The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a 'disarming' strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.
Assuntos
Ritmo Circadiano/imunologia , Inflamação/metabolismo , Neutrófilos/metabolismo , Pneumonia/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Animais , Degranulação Celular/imunologia , Grânulos Citoplasmáticos/imunologia , Grânulos Citoplasmáticos/metabolismo , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Humanos , Inflamação/imunologia , Camundongos , Neutrófilos/imunologia , Pneumonia/complicações , Pneumonia/imunologia , Proteoma/imunologia , Proteoma/metabolismo , Síndrome do Desconforto Respiratório/imunologiaRESUMO
Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune and interleukin-1 (IL-1) receptor-dependent, caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6∆PMN) is sufficient to initiate IL-1 receptor-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigate the mechanisms controlling IL-1α/ß release from neutrophils by inhibiting caspase-8-dependent apoptosis and Ripk1-Ripk3-Mlkl-regulated necroptosis. Loss of Ripk1 accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6∆PMN mice. Ptpn6∆PMN neutrophils displayed increased p38 mitogen-activated protein kinase-dependent Ripk1-independent IL-1 and tumor necrosis factor production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 mitogen-activated protein kinase activation to control tumor necrosis factor and IL-1α/ß expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3-Mlkl-dependent cell death and concomitant IL-1α/ß release.
Assuntos
Apoptose/imunologia , Caspase 8/imunologia , Neutrófilos/imunologia , Proteínas Quinases/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Animais , Caspase 8/genética , Células Cultivadas , Deleção de Genes , Inflamação/imunologia , Interleucina-1/imunologia , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Receptores Tipo I de Interleucina-1/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Sepsis is a biphasic disease characterized by an acute inflammatory response, followed by a prolonged immunosuppressive phase. Therapies aimed at controlling inflammation help to reduce the time patients with sepsis spend in intensive care units, but they do not lead to a reduction in overall mortality. Recently, the focus has been on addressing the immunosuppressive phase, often caused by apoptosis of immune cells. However, molecular triggers of these events are not yet known. Using whole-genome CRISPR screening in mice, we identified a triggering receptor expressed on myeloid cells (TREM) family receptor, TREML4, as a key regulator of inflammation and immune cell death in sepsis. Genetic ablation of Treml4 in mice demonstrated that TREML4 regulates calcium homeostasis, the inflammatory cytokine response, myeloperoxidase activation, the endoplasmic reticulum stress response and apoptotic cell death in innate immune cells, leading to an overall increase in survival rate, both during the acute and chronic phases of polymicrobial sepsis.