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1.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201048

RESUMO

The airways of patients with primary ciliary dyskinesia (PCD) contain persistently elevated neutrophil numbers and CXCL8 levels. Despite their abundance, neutrophils fail to clear the airways from bacterial infections. We investigated whether neutrophil functions are altered in patients with PCD. Neutrophils from patients and healthy controls (HC) were isolated from peripheral blood and exposed to various bacterial stimuli or cytokines. Neutrophils from patients with PCD were less responsive to low levels of fMLF in three different chemotaxis assays (p < 0.05), but expression of the fMLF receptors was unaltered. PCD neutrophils showed normal phagocytic function and expression of adhesion molecules. However, PCD neutrophils produced less reactive oxygen species upon stimulation with bacterial products or cytokines compared to HC neutrophils (p < 0.05). Finally, the capacity to release DNA, as observed during neutrophil extracellular trap formation, seemed to be reduced in patients with PCD compared to HC (p = 0.066). These results suggest that peripheral blood neutrophils from patients with PCD, in contrast to those of patients with cystic fibrosis or COPD, do not show features of over-activation, neither on baseline nor after stimulation. If these findings extend to lung-resident neutrophils, the reduced neutrophil activity could possibly contribute to the recurrent respiratory infections in patients with PCD.


Assuntos
Anti-Infecciosos/metabolismo , Bactérias/metabolismo , Quimiotaxia , Transtornos da Motilidade Ciliar/patologia , Citocinas/metabolismo , Neutrófilos/patologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/imunologia , Transtornos da Motilidade Ciliar/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Adulto Jovem
2.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201758

RESUMO

Neutrophils-once considered as simple killers of pathogens and unexciting for cancer research-are now acknowledged for their role in the process of tumorigenesis. Neutrophils are recruited to the tumor microenvironment where they turn into tumor-associated neutrophils (TANs), and are able to initiate and promote tumor progression and metastasis. Conversely, anti-tumorigenic properties of neutrophils have been documented, highlighting the versatile nature and high pleiotropic plasticity of these polymorphonuclear leukocytes (PMN-L). Here, we dissect the ambivalent roles of TANs in cancer and focus on selected functional aspects that could be therapeutic targets. Indeed, the critical point of targeting TAN functions lies in the fact that an immunosuppressive state could be induced, resulting in unwanted side effects. A deeper knowledge of the mechanisms linked to diverse TAN functions in different cancer types is necessary to define appropriate therapeutic strategies that are able to induce and maintain an anti-tumor microenvironment.


Assuntos
Carcinogênese/patologia , Terapia de Alvo Molecular/métodos , Neoplasias/patologia , Neutrófilos/patologia , Microambiente Tumoral/imunologia , Animais , Carcinogênese/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Neutrófilos/imunologia
3.
Cells ; 10(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208037

RESUMO

Neutrophils are the most abundant circulating innate immune cells and comprise the first immune defense line, as they are the most rapidly recruited cells at sites of infection or inflammation. Their main microbicidal mechanisms are degranulation, phagocytosis, cytokine secretion and the formation of extracellular traps. Neutrophil extracellular traps (NETs) are a microbicidal mechanism that involves neutrophil death. Since their discovery, in vitro and in vivo neutrophils have been challenged with a range of stimuli capable of inducing or inhibiting NET formation, with the objective to understand its function and regulation in health and disease. These networks composed of DNA and granular components are capable of immobilizing and killing pathogens. They comprise enzymes such as myeloperoxidase, elastase, cathepsin G, acid hydrolases and cationic peptides, all with antimicrobial and antifungal activity. Therefore, the excessive formation of NETs can also lead to tissue damage and promote local and systemic inflammation. Based on this concept, in this review, we focus on the role of NETs in different infectious and inflammatory diseases of the mucosal epithelia and skin.


Assuntos
Armadilhas Extracelulares/fisiologia , Membrana Mucosa/imunologia , Dermatopatias/imunologia , Células Epiteliais/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/fisiologia , Neutrófilos/imunologia , Neutrófilos/fisiologia , Dermatopatias/patologia
4.
Bone Joint J ; 103-B(7 Supple B): 135-144, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34192911

RESUMO

AIMS: Aseptic loosening is a leading cause of uncemented arthroplasty failure, often accompanied by fibrotic tissue at the bone-implant interface. A biological target, neutrophil extracellular traps (NETs), was investigated as a crucial connection between the innate immune system's response to injury, fibrotic tissue development, and proper bone healing. Prevalence of NETs in peri-implant fibrotic tissue from aseptic loosening patients was assessed. A murine model of osseointegration failure was used to test the hypothesis that inhibition (through Pad4-/- mice that display defects in peptidyl arginine deiminase 4 (PAD4), an essential protein required for NETs) or resolution (via DNase 1 treatment, an enzyme that degrades the cytotoxic DNA matrix) of NETs can prevent osseointegration failure and formation of peri-implant fibrotic tissue. METHODS: Patient peri-implant fibrotic tissue was analyzed for NETs biomarkers. To enhance osseointegration in loose implant conditions, an innate immune system pathway (NETs) was either inhibited (Pad4-/- mice) or resolved with a pharmacological agent (DNase 1) in a murine model of osseointegration failure. RESULTS: NETs biomarkers were identified in peri-implant fibrotic tissue collected from aseptic loosening patients and at the bone-implant interface in a murine model of osseointegration failure. Inhibition (Pad4-/- ) or resolution (DNase 1) of NETs improved osseointegration and reduced fibrotic tissue despite loose implant conditions in mice. CONCLUSION: This study identifies a biological target (NETs) for potential noninvasive treatments of aseptic loosening by discovering a novel connection between the innate immune system and post-injury bone remodelling caused by implant loosening. By inhibiting or resolving NETs in an osseointegration failure murine model, fibrotic tissue encapsulation around an implant is reduced and osseointegration is enhanced, despite loose implant conditions. Cite this article: Bone Joint J 2021;103-B(7 Supple B):135-144.


Assuntos
Desoxirribonuclease I/imunologia , Armadilhas Extracelulares/imunologia , Osseointegração/fisiologia , Proteína-Arginina Desiminase do Tipo 4/imunologia , Tíbia/cirurgia , Animais , Interface Osso-Implante , Modelos Animais de Doenças , Fibrose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Falha de Prótese
5.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065210

RESUMO

Previous studies have shown that COVID-19 leads to thrombotic complications, which have been associated with high morbidity and mortality rates. Neutrophils are the largest population of white blood cells and play a pivotal role in innate immunity. During an infection, neutrophils migrate from circulation to the infection site, contributing to killing pathogens. This mechanism is regulated by chemokines such as IL-8. Moreover, it was shown that neutrophils play an important role in thromboinflammation. Through a diverse repertoire of mechanisms, neutrophils, apart from directly killing pathogens, are able to activate the formation of thrombi. In COVID-19 patients, neutrophil activation promotes neutrophil extracellular trap (NET) formation, platelet aggregation, and cell damage. Furthermore, neutrophils participate in the pathogenesis of endothelitis. Overall, this review summarizes recent progress in research on the pathogenesis of COVID-19, highlighting the role of the prothrombotic action of neutrophils in NET formation.


Assuntos
COVID-19/imunologia , Armadilhas Extracelulares/imunologia , Imunidade Inata , Pulmão/imunologia , Neutrófilos/imunologia , Trombose/imunologia , COVID-19/complicações , COVID-19/patologia , COVID-19/terapia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/virologia , Armadilhas Extracelulares/virologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Rim/citologia , Rim/imunologia , Rim/patologia , Rim/virologia , Pulmão/citologia , Pulmão/patologia , Pulmão/virologia , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/virologia , SARS-CoV-2 , Trombose/complicações , Trombose/patologia , Trombose/virologia
6.
Biomolecules ; 11(5)2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066385

RESUMO

SARS-CoV-2 is a member of the family of coronaviruses associated with severe outbreaks of respiratory diseases in recent decades and is the causative agent of the COVID-19 pandemic. The recognition by and activation of the innate immune response recruits neutrophils, which, through their different mechanisms of action, form extracellular neutrophil traps, playing a role in infection control and trapping viral, bacterial, and fungal etiological agents. However, in patients with COVID-19, activation at the vascular level, combined with other cells and inflammatory mediators, leads to thrombotic events and disseminated intravascular coagulation, thus leading to a series of clinical manifestations in cerebrovascular, cardiac, pulmonary, and kidney disease while promoting severe disease and mortality. Previous studies of hospitalized patients with COVID-19 have shown that elevated levels of markers specific for NETs, such as free DNA, MPO, and H3Cit, are strongly associated with the total neutrophil count; with acute phase reactants that include CRP, D-dimer, lactate dehydrogenase, and interleukin secretion; and with an increased risk of severe COVID-19. This study analyzed the interactions between NETs and the activation pathways involved in immunothrombotic processes in patients with COVID-19.


Assuntos
COVID-19/patologia , Armadilhas Extracelulares/metabolismo , Trombose/imunologia , Trombose/patologia , Biomarcadores/metabolismo , COVID-19/imunologia , COVID-19/virologia , Proteínas do Sistema Complemento/metabolismo , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/patologia , Humanos , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , SARS-CoV-2/isolamento & purificação , Trombose/metabolismo
7.
Medicine (Baltimore) ; 100(23): e26288, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115032

RESUMO

ABSTRACT: The leukocytes play an important role in immune function during sepsis. We performed a retrospective study to investigate if leukocytes kinetics was associated with survival in critically ill patients with septic shock in intensive care unit (ICU).Patients with septic shock from January 1, 2014 to June 30, 2018 in our ICU were included. We extracted the demographic, clinical and laboratory data, comorbidities from our clinical database. The number of white blood cell, neutrophil and lymphocyte on day 1 and day 3 after diagnosis were collected and neutrophil to lymphocyte ratios (NLR) were calculated. Our primary outcome was 28-day mortality. Univariate and multivariate logistic regression models and cox proportional risk model were used to analyze the association between the leukocytes kinetics during first 3 days after ICU admission and the day-28 mortality.A total of 1245 septic shock patients with a 28-day mortality of 35.02% were included into analysis. There were no significant difference of lymphocyte number (0.83 ±â€Š0.02 vs 0.80 ±â€Š0.04, P = .552) between survival and non-survivals on day 1. However, the lymphocyte counts was significantly lower (0.95 ±â€Š0.03 vs 0.85 ±â€Š0.04, P = .024) on the third day. Both multivariate logistic and Cox regression analysis showed that lymphocyte counts on day 3 were associated with day-28 mortality. Moreover, Kaplan-Meier survival analysis revealed that increasing in lymphocyte counts and decreasing WBC, neutrophils and NLR during the first 3 days after diagnosis were associated with longer survival.Leukocytes kinetics during the first 3 days is a valuable prognostic marker in patients with septic shock in the ICU.


Assuntos
Ensaios de Migração Celular/métodos , Contagem de Leucócitos , Linfócitos/imunologia , Neutrófilos/imunologia , Choque Séptico , China , Cuidados Críticos/métodos , Estado Terminal/terapia , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Estimativa de Kaplan-Meier , Contagem de Leucócitos/métodos , Contagem de Leucócitos/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Choque Séptico/diagnóstico , Choque Séptico/imunologia , Choque Séptico/mortalidade
8.
Medicine (Baltimore) ; 100(23): e26292, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115033

RESUMO

ABSTRACT: Minute clear cell renal cell carcinoma (MccRCC) has a diameter of <1.5 cm and can be diagnosed using multi-slice spiral CT (MSCT). Recently, the role of the neutrophil-lymphocyte ratio (NLR) in the development of MccRCC has attracted attention. This study aimed to further explore the relationship between the NLR and MccRCC.This was a prospective study of 100 patients who were diagnosed with MccRCC using MSCT at Urumqi Friendship Hospital, China. The study investigated a series of pretreatment factors, including NLR and patients' general clinical data. Statistical methods employed included Pearson's chi-square test, Spearman-rho correlation test, Cox regression analysis, and receiver operator characteristic curve analysis.Based on Pearson's χ2, Spearman-rho test, and univariate/multivariate Cox regression analysis, the overall survival of patients with MccRCC was shown to be significantly related to NLR (P < .001). NLR (hazard ratio = 50.676, 95%CI, 17.543-146.390, P < .001) is a significant independent risk-factor for MccRCC. A receiver operator characteristic curve was plotted to examine specificity and sensitivity between NLR and MccRCC (area under curve = 0.958, P < .001).The level of the NLR plays a crucial role in the survival of patients with MccRCC, as diagnosed with MSCT. The higher the NLR, the worse the prognosis for patients with MccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Linfócitos/imunologia , Neutrófilos/imunologia , Tomografia Computadorizada Espiral/métodos , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , China , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/sangue , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Contagem de Leucócitos/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Sensibilidade e Especificidade
9.
Front Immunol ; 12: 678771, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149714

RESUMO

Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , COVID-19/imunologia , Humanos , SARS-CoV-2
10.
Front Immunol ; 12: 680134, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149717

RESUMO

Whilst the majority of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of COVID-19, experience mild to moderate symptoms, approximately 20% develop severe respiratory complications that may progress to acute respiratory distress syndrome, pulmonary failure and death. To date, single cell and high-throughput systems based analyses of the peripheral and pulmonary immune responses to SARS-CoV-2 suggest that a hyperactive and dysregulated immune response underpins the development of severe disease, with a prominent role assigned to neutrophils. Characterised in part by robust generation of neutrophil extracellular traps (NETs), the presence of immature, immunosuppressive and activated neutrophil subsets in the circulation, and neutrophilic infiltrates in the lung, a granulocytic signature is emerging as a defining feature of severe COVID-19. Furthermore, an assessment of the number, maturity status and/or function of circulating neutrophils at the time of hospital admission has shown promise as a prognostic tool for the early identification of patients at risk of clinical deterioration. Here, by summarising the results of studies that have examined the peripheral and pulmonary immune response to SARS-CoV-2, we provide a comprehensive overview of the changes that occur in the composition, phenotype and function of the neutrophil pool in COVID-19 patients of differing disease severities and discuss potential mediators of SARS-CoV-2-induced neutrophil dysfunction. With few specific treatments currently approved for COVID-19, we conclude the review by discussing whether neutrophils represent a potential therapeutic target for the treatment of patients with severe COVID-19.


Assuntos
COVID-19/imunologia , Neutrófilos/imunologia , SARS-CoV-2/imunologia , Armadilhas Extracelulares/imunologia , Humanos
11.
Science ; 372(6548)2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34140358

RESUMO

Neutrophils communicate with each other to form swarms in infected organs. Coordination of this population response is critical for the elimination of bacteria and fungi. Using transgenic mice, we found that neutrophils have evolved an intrinsic mechanism to self-limit swarming and avoid uncontrolled aggregation during inflammation. G protein-coupled receptor (GPCR) desensitization acts as a negative feedback control to stop migration of neutrophils when they sense high concentrations of self-secreted attractants that initially amplify swarming. Interference with this process allows neutrophils to scan larger tissue areas for microbes. Unexpectedly, this does not benefit bacterial clearance as containment of proliferating bacteria by neutrophil clusters becomes impeded. Our data reveal how autosignaling stops self-organized swarming behavior and how the finely tuned balance of neutrophil chemotaxis and arrest counteracts bacterial escape.


Assuntos
Quimiotaxia de Leucócito , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Linfonodos/microbiologia , Neutrófilos/fisiologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Animais , Agregação Celular , Quimiocina CXCL2 , Eosinófilos/fisiologia , Feminino , Quinase 2 de Receptor Acoplado a Proteína G/genética , Inflamação , Leucotrieno B4/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neutrófilos/imunologia , Infecções por Pseudomonas/microbiologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Pele/imunologia , Pele/lesões , Pele/patologia
12.
Nat Commun ; 12(1): 3612, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127676

RESUMO

Widespread circulation of SARS-CoV-2 in humans raises the theoretical risk of reverse zoonosis events with wildlife, reintroductions of SARS-CoV-2 into permissive nondomesticated animals. Here we report that North American deer mice (Peromyscus maniculatus) are susceptible to SARS-CoV-2 infection following intranasal exposure to a human isolate, resulting in viral replication in the upper and lower respiratory tract with little or no signs of disease. Further, shed infectious virus is detectable in nasal washes, oropharyngeal and rectal swabs, and viral RNA is detectable in feces and occasionally urine. We further show that deer mice are capable of transmitting SARS-CoV-2 to naïve deer mice through direct contact. The extent to which these observations may translate to wild deer mouse populations remains unclear, and the risk of reverse zoonosis and/or the potential for the establishment of Peromyscus rodents as a North American reservoir for SARS-CoV-2 remains unknown.


Assuntos
COVID-19/veterinária , Peromyscus/virologia , Zoonoses/transmissão , Animais , Animais Selvagens , Anticorpos Neutralizantes/imunologia , COVID-19/patologia , COVID-19/transmissão , Suscetibilidade a Doenças , Fezes/virologia , Feminino , Histiócitos/patologia , Humanos , Masculino , Neutrófilos/imunologia , Neutrófilos/patologia , RNA Viral/isolamento & purificação , SARS-CoV-2/classificação , SARS-CoV-2/genética , Estados Unidos , Zoonoses/virologia
13.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(1): 123-130, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-34117844

RESUMO

Bronchial asthma is a chronic respiratory disease,characterized by airway inflammation,airway hyperresponsiveness,reversible airway obstruction and airway remodeling,in which a variety of cells including airway inflammatory cells and structural cells are involved. Previous studies have shown that asthma is mainly driven by Th2 cytokines IL-4,IL-5,and IL-13,leading to airway eosinophil inflammation. With further research,however,it has been found that neutrophils are also closely related to asthma. Numbers of neutrophils are elevated in airway through increased chemotaxis and decreased apoptosis,which is earlier than eosinophils,leading to airway neutrophilic inflammation. Neutrophils can produce elastase,myeloperoxidase,neutrophil extra- cellular traps,chemokines and cytokines,participating in the occurrence and development of asthma. The antagonists against these molecules,such as anti-IL-8 receptor antibody,anti-IL-17 antibody,and DNase,have shown positive effects on neutrophilic asthma,but further studies are needed to support their clinical application. This article mainly reviews the role of neutrophils in asthma and related mechanisms.


Assuntos
Asma , Neutrófilos , Asma/imunologia , Citocinas , Eosinófilos , Humanos , Inflamação , Neutrófilos/imunologia
14.
JCI Insight ; 6(13)2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34143756

RESUMO

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 pathology.


Assuntos
Artrite Reumatoide/imunologia , COVID-19/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Osteopontina/imunologia , Artrite Reumatoide/metabolismo , Antígeno B7-H1/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Antígeno CD48/imunologia , COVID-19/induzido quimicamente , COVID-19/metabolismo , Proteínas de Ligação a Ácido Graxo/imunologia , Humanos , Lectinas/imunologia , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Glicoproteínas de Membrana/imunologia , Monócitos/metabolismo , Neutrófilos/metabolismo , Osteopontina/sangue , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Imunológicos/imunologia , Proteína S100A12/imunologia , Proteína S100A12/metabolismo , Membrana Sinovial/imunologia , Tomografia Computadorizada por Raios X
15.
Nat Commun ; 12(1): 3739, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145258

RESUMO

Serum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs-/- mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs-/- mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus.


Assuntos
Aspergillus fumigatus/imunologia , Aspergilose Pulmonar Invasiva/imunologia , Neutrófilos/imunologia , Componente Amiloide P Sérico/genética , Animais , Células Cultivadas , Variação Genética/genética , Humanos , Imunidade Inata/imunologia , Hospedeiro Imunocomprometido/imunologia , Aspergilose Pulmonar Invasiva/patologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/imunologia
16.
FASEB J ; 35(7): e21746, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34151465

RESUMO

Bullous pemphigoid (BP), an autoimmune skin disease, is characterized by autoantibodies against hemidesmosomal proteins in the skin and mucous membranes. Neutrophils infiltrate BP skin lesions, however, their role in immune dysregulation remains unclear. We investigated whether BP involves aberrant neutrophil extracellular traps (NETs) formation in skin lesions and circulation; and examined the triggers and deleterious immuno-inflammatory consequences. In the present study, we found that circulating NET-related biomarker levels increased in serum and blister fluid of BP patients and significantly correlated with disease severity. Additionally, circulating neutrophils from BP patients displayed enhanced spontaneous NETs formation than healthy controls. In vitro, BP180-NC16A immune complexes-induced NETosis in neutrophils from BP patients, which was abrogated by Fcγ receptor and/or NADPH pathway blockade. Furthermore, the elevated levels of NETs from BP patients boosted autoantibody production by inducing B-cell differentiation into plasma cells, mediated by MAPK P38 cascade activation. Together, our findings provide strong evidence that NETs are involved in a pathogenic loop, causing excessive differentiation of B cells and promotion of autoantibody production. Hence, targeting aberrant neutrophil responses will provide novel potential targets for the treatment of BP.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Penfigoide Bolhoso/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linfócitos B/metabolismo , Biomarcadores/metabolismo , Vesícula/imunologia , Vesícula/metabolismo , Armadilhas Extracelulares/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Neutrófilos/metabolismo , Penfigoide Bolhoso/metabolismo , Plasmócitos/imunologia , Plasmócitos/metabolismo , Receptores de IgG/imunologia , Transdução de Sinais/imunologia , Pele/imunologia , Pele/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Proc Natl Acad Sci U S A ; 118(27)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34183391

RESUMO

IgA is the second most abundant antibody present in circulation and is enriched at mucosal surfaces. As such, IgA plays a key role in protection against a variety of mucosal pathogens including viruses. In addition to neutralizing viruses directly, IgA can also stimulate Fc-dependent effector functions via engagement of Fc alpha receptors (Fc-αRI) expressed on the surface of certain immune effector cells. Neutrophils are the most abundant leukocyte, express Fc-αRI, and are often the first to respond to sites of injury and infection. Here, we describe a function for IgA-virus immune complexes (ICs) during viral infections. We show that IgA-virus ICs potentiate NETosis-the programmed cell-death pathway through which neutrophils release neutrophil extracellular traps (NETs). Mechanistically, IgA-virus ICs potentiated a suicidal NETosis pathway via engagement of Fc-αRI on neutrophils through a toll-like receptor-independent, NADPH oxidase complex-dependent pathway. NETs also were capable of trapping and inactivating viruses, consistent with an antiviral function.


Assuntos
Armadilhas Extracelulares/imunologia , Imunoglobulina A/imunologia , Neutrófilos/imunologia , Viroses/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antígenos CD/metabolismo , Armadilhas Extracelulares/virologia , Humanos , Influenzavirus A/imunologia , NADPH Oxidases/metabolismo , Neutrófilos/patologia , Neutrófilos/virologia , Receptores Fc/metabolismo , SARS-CoV-2/imunologia , Transdução de Sinais , Vírion
18.
Viruses ; 13(5)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064802

RESUMO

The role of the adaptive microenvironment components in severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection is widely researched, but remains unclear. Studying the common dynamics of adaptive immune response changes can help understand the pathogenesis of coronavirus disease 2019 (COVID-19), especially in critical patients. The aim of the present study was to determine the cytokines concentration and leukocyte subpopulations profiles in the severe COVID-19 (n = 23) and critical (n = 18) COVID-19 group distinguished by the computed tomography (CT) severity score. We observed lower percentage of lymphocyte subpopulation, higher neutrophils to lymphocytes ratio (NLR) and higher IL-6 concentration in critical COVID-19 group than in severe group. CT severity score was negative correlated with proportion of lymphocytes, lymphocytes T, CD4+ cells, Treg cells and NK cells and positive correlated with neutrophils, NLR, and IL-6. In critical group more correlations between cytokines and lymphocytes were observed, mainly between TNF-α, IL-1ß and lymphocyte subpopulations. The collective assessment of the cytokine profile, leukocyte subpopulations and the CT severity score can help to characterize and differentiate patient in advanced COVID-19 than the study of single parameters. We have shown that the interconnection of elements of the adaptive microenvironment can play an important role in critical COVID-19 cases.


Assuntos
COVID-19/imunologia , Citocinas/análise , Leucócitos/citologia , Adulto , Idoso , COVID-19/metabolismo , Citocinas/imunologia , Feminino , Humanos , Interleucina-1beta/imunologia , Células Matadoras Naturais/imunologia , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Linfócitos T Reguladores/imunologia , Tomografia Computadorizada por Raios X , Fator de Necrose Tumoral alfa/imunologia
19.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073872

RESUMO

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Amidas/farmacologia , Citocinas/metabolismo , Etanolaminas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Amidas/uso terapêutico , Animais , Etanolaminas/uso terapêutico , Imuno-Histoquímica , Inflamação/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ácidos Palmíticos/uso terapêutico , Peroxidase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Front Immunol ; 12: 700429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177967

RESUMO

The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and "cytokine storm". The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response.


Assuntos
Anti-Inflamatórios/farmacologia , Antígenos CD/metabolismo , COVID-19/terapia , Síndrome da Liberação de Citocina/terapia , Imunoglobulinas Intravenosas/farmacologia , Neutrófilos/imunologia , Receptores Fc/metabolismo , Receptores de IgG/metabolismo , SARS-CoV-2/fisiologia , Anticorpos Antivirais/metabolismo , Complexo Antígeno-Anticorpo , Linhagem Celular , Humanos , Imunização Passiva , Imunomodulação , Fagocitose , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/metabolismo
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