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1.
FASEB J ; 35(5): e21577, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33831263

RESUMO

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is an emerging respiratory pathogen that has rapidly spread in human populations. Severe forms of infection associate cytokine release syndrome and acute lung injury due to hyperinflammatory responses even though virus clearance is achieved. Key components of inflammation include immune cell recruitment in infected tissues, a step which is under the control of endothelial cells. Here, we review endothelial cell responses in inflammation and infection due to SARS-CoV-2 together with phenotypic and functional alterations of monocytes, T and B lymphocytes with which they interact. We surmise that endothelial cells function as an integrative and active platform for the various cells recruited, where fine tuning of immune responses takes place and which provides opportunities for therapeutic intervention.


Assuntos
Imunidade Adaptativa/imunologia , /patologia , Células Endoteliais/patologia , Células Mieloides/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Citocinas/imunologia , Humanos , Memória Imunológica , Células Mieloides/citologia , Linfócitos T/citologia , Linfócitos T/imunologia
2.
Cancer J ; 27(2): 119-125, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33750071

RESUMO

ABSTRACT: The successful application of chimeric antigen receptor (CAR) T cells for the treatment of relapsed and refractory B-cell malignancies has ushered in a new frontier for the immunotherapy of cancer. Despite its successes, CAR T-cell therapy presents several challenges. Cytokine release syndrome (CRS) triggered by robust and exponential CAR T-cell expansion is the most common adverse effect and may be severe or life-threatening. Although modulation of the interleukin 6 axis was appreciated early on as a means to manage CRS, the exact underlying mechanisms leading to severe CRS remain to be elucidated. What is clear is that severe CRS involves recruitment of the broader immune system into a hyperinflammatory and unregulated state. Myeloid-derived cells appear to play a critical role in this regard and are at the center of active investigation. In this article, we will focus on important elements of CRS, the clinical manifestations, underlying biology, and management strategies including grading, supportive care, and treatment via immunosuppression.


Assuntos
Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Imunoterapia Adotiva/efeitos adversos , Animais , Modelos Animais de Doenças , Humanos , Imunoterapia Adotiva/métodos , Camundongos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/patologia
3.
Front Immunol ; 12: 627548, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777012

RESUMO

Background: Emerging evidence argues that monocytes, circulating innate immune cells, are principal players in COVID-19 pneumonia. The study aimed to investigate the role of soluble (s)CD163 and sCD14 plasmatic levels in predicting disease severity and characterize peripheral blood monocytes and dendritic cells (DCs), in patients with COVID-19 pneumonia (COVID-19 subjects). Methods: On admission, in COVID-19 subjects sCD163 and sCD14 plasmatic levels, and peripheral blood monocyte and DC subsets were compared to healthy donors (HDs). According to clinical outcome, COVID-19 subjects were divided into ARDS and non-ARDS groups. Results: Compared to HDs, COVID-19 subjects showed higher sCD163 (p<0.0001) and sCD14 (p<0.0001) plasmatic levels. We observed higher sCD163 plasmatic levels in the ARDS group compared to the non-ARDS one (p=0.002). The cut-off for sCD163 plasmatic level greater than 2032 ng/ml was predictive of disease severity (AUC: 0.6786, p=0.0022; sensitivity 56.7% [CI: 44.1-68.4] specificity 73.8% [CI: 58.9-84.7]). Positive correlation between plasmatic levels of sCD163, LDH and IL-6 and between plasmatic levels of sCD14, D-dimer and ferritin were found. Compared to HDs, COVID-19 subjects showed lower percentages of non-classical (p=0.0012) and intermediate monocytes (p=0.0447), slanDCs (p<0.0001), myeloid DCs (mDCs, p<0.0001), and plasmacytoid DCs (pDCs, p=0.0014). Compared to the non-ARDS group, the ARDS group showed lower percentages of non-classical monocytes (p=0.0006), mDCs (p=0.0346), and pDCs (p=0.0492). Conclusions: The increase in sCD163 and sCD14 plasmatic levels, observed on hospital admission in COVID-19 subjects, especially in those who developed ARDS, and the correlations of these monocyte/macrophage activation markers with typical inflammatory markers of COVID-19 pneumonia, underline their potential use to assess the risk of progression of the disease. In an early stage of the disease, the assessment of sCD163 plasmatic levels could have clinical utility in predicting the severity of COVID-19 pneumonia.


Assuntos
Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Células Dendríticas/imunologia , Receptores de Lipopolissacarídeos/sangue , Monócitos/imunologia , Células Mieloides/imunologia , Receptores de Superfície Celular/sangue , /imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , /diagnóstico , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Progressão da Doença , Feminino , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/virologia , Células Mieloides/metabolismo , Células Mieloides/virologia , Admissão do Paciente , Fenótipo , Índice de Gravidade de Doença , Regulação para Cima
4.
Nat Commun ; 12(1): 1428, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674591

RESUMO

Since the beginning of the SARS-CoV-2 pandemic, COVID-19 appeared as a unique disease with unconventional tissue and systemic immune features. Here we show a COVID-19 immune signature associated with severity by integrating single-cell RNA-seq analysis from blood samples and broncho-alveolar lavage fluids with clinical, immunological and functional ex vivo data. This signature is characterized by lung accumulation of naïve lymphoid cells associated with a systemic expansion and activation of myeloid cells. Myeloid-driven immune suppression is a hallmark of COVID-19 evolution, highlighting arginase-1 expression with immune regulatory features of monocytes. Monocyte-dependent and neutrophil-dependent immune suppression loss is associated with fatal clinical outcome in severe patients. Additionally, our analysis shows a lung CXCR6+ effector memory T cell subset is associated with better prognosis in patients with severe COVID-19. In summary, COVID-19-induced myeloid dysregulation and lymphoid impairment establish a condition of 'immune silence' in patients with critical COVID-19.


Assuntos
/imunologia , /imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Células Mieloides/imunologia , Neutrófilos/imunologia , Linfócitos T/imunologia
5.
Science ; 371(6535)2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33737461

RESUMO

Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Rα form a composite surface to engage the shared signaling receptor IL-10Rß, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rß binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8+ T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.


Assuntos
Interleucina-10/química , Interleucina-10/metabolismo , Animais , Sítios de Ligação , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Microscopia Crioeletrônica , Citocinas/metabolismo , Evolução Molecular Direcionada , Humanos , Inflamação , Interleucina-10/agonistas , Subunidade alfa de Receptor de Interleucina-10/química , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Subunidade beta de Receptor de Interleucina-10/química , Subunidade beta de Receptor de Interleucina-10/metabolismo , Ativação de Macrófagos , Camundongos , Modelos Moleculares , Monócitos/imunologia , Monócitos/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Ligação Proteica , Engenharia de Proteínas , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Fator de Transcrição STAT3/metabolismo , Sepse/imunologia , Transdução de Sinais
6.
Int Immunol ; 33(4): 241-247, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33538817

RESUMO

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.


Assuntos
/patologia , Interleucina-8/sangue , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , /imunologia , Humanos , Interleucina-8/imunologia , Japão , Contagem de Leucócitos , Células Mieloides/imunologia , Ativação de Neutrófilo/imunologia
7.
Science ; 371(6529): 595-602, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33542131

RESUMO

Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Transplante de Microbiota Fecal , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/terapia , Linfócitos T CD8-Positivos/imunologia , Microbioma Gastrointestinal , Humanos , Interleucina-8/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Células Mieloides/imunologia , Microambiente Tumoral/imunologia
8.
Nature ; 590(7844): 122-128, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33473210

RESUMO

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.


Assuntos
Envelhecimento/metabolismo , Disfunção Cognitiva/prevenção & controle , Células Mieloides/metabolismo , Adulto , Idoso , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Respiração Celular , Células Cultivadas , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/genética , Dinoprostona/metabolismo , Metabolismo Energético , Glucose/metabolismo , Glicogênio/biossíntese , Glicogênio/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Transtornos da Memória/tratamento farmacológico , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/metabolismo , Mitocôndrias/metabolismo , Células Mieloides/imunologia , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP2/deficiência , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
9.
Nat Microbiol ; 6(1): 73-86, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340034

RESUMO

Non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (COVID-19) to clinical trials. Here, we compare acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old rhesus macaques, baboons and old marmosets. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage was increased in old versus young baboons. Using techniques including computed tomography imaging, immunophenotyping, and alveolar/peripheral cytokine response and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent type-I interferon response. Macaques developed T-cell memory phenotypes/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young macaques. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.


Assuntos
/veterinária , Callithrix/imunologia , Pulmão/imunologia , Macaca mulatta/imunologia , Doenças dos Macacos/virologia , Papio/imunologia , /imunologia , Imunidade Adaptativa , Animais , Anticorpos Antivirais/imunologia , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar , /imunologia , Feminino , Humanos , Imunidade Celular/imunologia , Imunoglobulina G/imunologia , Inflamação/patologia , Pulmão/virologia , Masculino , Doenças dos Macacos/imunologia , Células Mieloides/imunologia , Carga Viral , Eliminação de Partículas Virais
10.
Int J Mol Sci ; 22(1)2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33375505

RESUMO

For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Macrófagos/metabolismo , Microglia/citologia , Microglia/metabolismo , Animais , Neoplasias Encefálicas/patologia , Progressão da Doença , Glioblastoma/imunologia , Glioblastoma/patologia , Glioma/imunologia , Glioma/metabolismo , Glioma/patologia , Humanos , Antígenos Comuns de Leucócito/metabolismo , Células Mieloides/citologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Microambiente Tumoral
11.
Front Immunol ; 11: 2145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983174

RESUMO

SARS-CoV-2 infection has recently been declared a pandemic. Some patients showing severe symptoms exhibit drastic inflammation and airway damage. In this study, we re-analyzed published scRNA-seq data of COVID-19 patient bronchoalveolar lavage fluid to further classify and compare immunological features according to the patient's disease severity. Patients with severe symptoms showed DNA damage and apoptotic features of epithelial cells. Our results suggested that epithelial damage was associated with neutrophil infiltration. Myeloid cells of severe patients showed higher expression of proinflammatory cytokines and chemokines such as CXCL8. As a result, neutrophils were abundant in lungs of patients from the severe group. Furthermore, recruited neutrophils highly expressed genes related to neutrophil extracellular traps. Neutrophil-mediated inflammation was regulated by glucocorticoid receptor expression and activity. Based on these results, we suggest that severe COVID-19 symptoms may be determined by differential expression of glucocorticoid receptors and neutrophils.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Interleucina-8/genética , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Receptores de Glucocorticoides/genética , Índice de Gravidade de Doença , Transcriptoma , Adulto , Idoso , Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/virologia , Células Epiteliais/patologia , Armadilhas Extracelulares/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação/imunologia , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Células Mieloides/imunologia , Infiltração de Neutrófilos/imunologia , Pandemias , Pneumonia Viral/virologia , RNA-Seq , Receptores de Glucocorticoides/metabolismo , Análise de Célula Única/métodos
12.
Nat Commun ; 11(1): 4035, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788578

RESUMO

Polyphosphates are linear polymers and ubiquitous metabolites. Bacterial polyphosphates are long chains of hundreds of phosphate units. Here, we report that mouse survival of peritoneal Escherichia coli sepsis is compromised by long-chain polyphosphates, and improves with bacterial polyphosphatekinase deficiency or neutralization using recombinant exopolyphosphatase. Polyphosphate activities are chain-length dependent, impair pathogen clearance, antagonize phagocyte recruitment, diminish phagocytosis and decrease production of iNOS and cytokines. Macrophages bind and internalize polyphosphates, in which their effects are independent of P2Y1 and RAGE receptors. The M1 polarization driven by E. coli derived LPS is misdirected by polyphosphates in favor of an M2 resembling phenotype. Long-chain polyphosphates modulate the expression of more than 1800 LPS/TLR4-regulated genes in macrophages. This interference includes suppression of hundreds of type I interferon-regulated genes due to lower interferon production and responsiveness, blunted STAT1 phosphorylation and reduced MHCII expression. In conclusion, prokaryotic polyphosphates disturb multiple macrophage functions for evading host immunity.


Assuntos
Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Escherichia coli/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Polifosfatos/metabolismo , Animais , Apresentação do Antígeno/imunologia , Polaridade Celular , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon Tipo I/metabolismo , Lipopolissacarídeos , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Fenótipo , Sepse/imunologia , Análise de Sobrevida , Transcriptoma/genética
13.
Cell ; 182(6): 1419-1440.e23, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32810438

RESUMO

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Células Mieloides/imunologia , Mielopoese , Pneumonia Viral/imunologia , Adulto , Idoso , Antígenos CD11/genética , Antígenos CD11/metabolismo , Células Cultivadas , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Feminino , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Células Mieloides/citologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Proteoma/genética , Proteoma/metabolismo , Proteômica , Análise de Célula Única
14.
Science ; 369(6508): 1210-1220, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32788292

RESUMO

Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. In the peripheral blood mononuclear cells (PBMCs) of COVID-19 patients, we observed reduced expression of human leukocyte antigen class DR (HLA-DR) and proinflammatory cytokines by myeloid cells as well as impaired mammalian target of rapamycin (mTOR) signaling and interferon-α (IFN-α) production by plasmacytoid dendritic cells. By contrast, we detected enhanced plasma levels of inflammatory mediators-including EN-RAGE, TNFSF14, and oncostatin M-which correlated with disease severity and increased bacterial products in plasma. Single-cell transcriptomics revealed a lack of type I IFNs, reduced HLA-DR in the myeloid cells of patients with severe COVID-19, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics and transient, low IFN-α levels in plasma during infection. These results reveal mechanisms and potential therapeutic targets for COVID-19.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Citocinas/sangue , DNA Bacteriano/sangue , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Citometria de Fluxo , Antígenos HLA-DR/análise , Humanos , Imunidade , Imunidade Inata , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Mediadores da Inflamação/sangue , Interferon Tipo I/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/sangue , Masculino , Células Mieloides/imunologia , Células Mieloides/metabolismo , Pandemias , Transdução de Sinais , Análise de Célula Única , Biologia de Sistemas , Serina-Treonina Quinases TOR/metabolismo , Transcrição Genética , Transcriptoma
15.
Nature ; 585(7823): 96-101, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32814898

RESUMO

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation1-3. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells4-6. Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72-/- mice show marked early activation of the type I interferon response, and C9orf72-/- myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72-/- myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72-/- immune cells as well as splenomegaly and inflammation in C9orf72-/- mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.


Assuntos
Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Inflamação/metabolismo , Inflamação/prevenção & controle , Proteínas de Membrana/metabolismo , Células Mieloides/metabolismo , Envelhecimento/imunologia , Esclerose Amiotrófica Lateral/genética , Animais , Proteína C9orf72/deficiência , Células Dendríticas/citologia , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Inflamação/genética , Inflamação/imunologia , Interferon Tipo I/biossíntese , Interferon Tipo I/imunologia , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Células Mieloides/imunologia , Neoplasias/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia
16.
Scand J Immunol ; 92(5): e12957, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32767789

RESUMO

Bone marrow haematopoietic stem and progenitor cells (HSPCs) express pattern recognition receptors such as Toll-like receptors (TLRs) to sense microbial products and activation of these innate immune receptors induces cytokine expression and redirects bone marrow haematopoiesis towards the increased production of myeloid cells. Secreted cytokines by HSPCs in response to TLR ligands can act in an autocrine or paracrine manner to regulate haematopoiesis. Moreover, tonic activation of HSPCs by microbiota-derived compounds might educate HSPCs to produce superior myeloid cells equipped with innate memory responses to combat pathogens. While haematopoietic stem cell activation through TLRs meets the increased demand for blood leucocytes to protect the host against infection, persistent exposure to inflammatory cytokines or microbial products might impair their function and even induce malignant transformation. This review highlights the potential outcomes of HSPCs in response to TLR ligands.


Assuntos
Células da Medula Óssea/imunologia , Células-Tronco Hematopoéticas/imunologia , Microbiota/imunologia , Células Mieloides/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/microbiologia , Citocinas/imunologia , Citocinas/metabolismo , Hematopoese/imunologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/microbiologia , Humanos , Células Mieloides/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo
17.
Med Hypotheses ; 143: 110122, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32759007

RESUMO

A characteristic feature of COVID-19 disease is lymphopenia. Lymphopenia occurs early in the clinical course and is a predictor of disease severity and outcomes. The mechanism of lymphopenia in COVID-19 is uncertain. It has been variously attributed to the release of inflammatory cytokines including IL-6 and TNF-α; direct infection of the lymphocytes by the virus; and rapid sequestration of lymphocytes in the tissues. Additionally, we postulate that prostaglandin D2 (PGD2) is a key meditator of lymphopenia in COVID-19. First, SARS-CoV infection is known to stimulate the production of PGD2 in the airways, which inhibits the host dendritic cell response via the DP1 receptor signaling. Second, PGD2 is known to upregulate monocytic myeloid-derived suppressor cells (MDSC) via the DP2 receptor signaling in group 2 innate lymphoid cells (ILC2). We propose targeting PGD2/DP2 signaling using a receptor antagonist such as ramatroban as an immunotherapy for immune dysfunction and lymphopenia in COVID-19 disease.


Assuntos
Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Linfopenia/fisiopatologia , Modelos Imunológicos , Terapia de Alvo Molecular , Pandemias , Pneumonia Viral/fisiopatologia , Prostaglandina D2/fisiologia , Sistema Respiratório/metabolismo , Adulto , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Criança , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Células Dendríticas/imunologia , Humanos , Linfopenia/etiologia , Células Mieloides/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Prostaglandina D2/biossíntese , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Receptores de Prostaglandina/fisiologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T/imunologia , Tromboxano A2/antagonistas & inibidores
18.
Nat Commun ; 11(1): 3798, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732867

RESUMO

Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicroscopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis.


Assuntos
Células Endoteliais/citologia , Endotélio Vascular/citologia , Linfonodos/irrigação sanguínea , Linfócitos/imunologia , Células Mieloides/imunologia , Animais , Sequência de Bases , Movimento Celular/imunologia , Feminino , Perfilação da Expressão Gênica , Homeostase/imunologia , Inflamação/imunologia , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Análise de Sequência de RNA , Análise de Célula Única , Transcriptoma/genética
19.
Scand J Immunol ; 92(5): e12963, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32851668

RESUMO

Myeloid cells represent the major cellular component of innate immune responses. Myeloid cells include monocytes and macrophages, granulocytes (neutrophils, basophils and eosinophils) and dendritic cells (DC). The role of myeloid cells has been broadly described both in physiological and in pathological conditions. All tissues or organs are equipped with resident myeloid cells, such as parenchymal microglia in the brain, which contribute to maintaining homeostasis. Moreover, in case of infection or tissue damage, other myeloid cells such as monocytes or granulocytes (especially neutrophils) can be recruited from the circulation, at first to promote inflammation and later to participate in repair and regeneration. This review aims to address the regulatory roles of myeloid cells in inflammatory diseases of the central nervous system (CNS), with a particular focus on recent work showing induction of suppressive function via stimulation of innate signalling in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE).


Assuntos
Sistema Nervoso Central/imunologia , Células Dendríticas/imunologia , Granulócitos/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Células Mieloides/imunologia , Animais , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia
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