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1.
Int J Biol Sci ; 20(2): 733-750, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38169726

RESUMO

Macrophage pyroptosis and neutrophil extracellular traps (NETs) play a critical role in sepsis pathophysiology; however, the role of macrophage pyroptosis in the regulation of NETs formation during sepsis is unknown. Here, we showed that macrophages transfer mitochondria to neutrophils through microvesicles following pyroptosis; this process induces mitochondrial dysfunction and triggers the induction of NETs formation through mitochondrial reactive oxygen species (mtROS)/Gasdermin D (GSDMD) axis. These pyroptotic macrophage-derived microvesicles can induce tissues damage, coagulation, and NETs formation in vivo. Disulfiram partly inhibits these effects in a mouse model of sepsis. Pyroptotic macrophage-derived microvesicles induce NETs formation through mitochondrial transfer, both in vitro and in vivo. Microvesicles-mediated NETs formation depends on the presence of GSDMD-N-expressing mitochondria in the microvesicles. This study elucidates a microvesicles-based pathway for NETs formation during sepsis and proposes a microvesicles-based intervention measure for sepsis management.


Assuntos
Armadilhas Extracelulares , Sepse , Camundongos , Animais , Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Mitocôndrias/metabolismo , Macrófagos/metabolismo , Sepse/metabolismo
2.
J Infect Dis ; 224(8): 1333-1344, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34374752

RESUMO

BACKGROUND: Lymphopenia is a key feature for adult patients with coronavirus disease 2019 (COVID-19), although it is rarely observed in children. The underlying mechanism remains unclear. METHODS: Immunohistochemical and flow cytometric analyses were used to compare the apoptotic rate of T cells from COVID-19 adults and children and apoptotic responses of adult and child T cells to COVID-19 pooled plasma. Biological properties of caspases and reactive oxygen species were assessed in T cells treated by COVID-19 pooled plasma. RESULTS: Mitochondria apoptosis of peripheral T cells were identified in COVID-19 adult patient samples but not in the children. Furthermore, increased tumor necrosis factor-α and interleukin-6 in COVID-19 plasma induced mitochondria apoptosis and caused deoxyribonucleic acid damage by elevating reactive oxygen species levels of the adult T cells. However, the child T cells showed tolerance to mitochondrial apoptosis due to mitochondria autophagy. Activation of autophagy could decrease apoptotic sensitivity of the adult T cells to plasma from COVID-19 patients. CONCLUSIONS: Our results indicated that the mitochondrial apoptosis pathway was activated in T cells of COVID-19 adult patients specifically, which may shed light on the pathophysiological difference between adults and children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ).


Assuntos
COVID-19/complicações , Linfopenia/sangue , SARS-CoV-2/imunologia , Linfócitos T/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Apoptose/imunologia , Autofagia , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Criança , Pré-Escolar , Humanos , Lactente , Linfopenia/imunologia , Linfopenia/patologia , Linfopenia/virologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/imunologia , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia
3.
J Immunol ; 207(1): 234-243, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34183366

RESUMO

T cell-interacting activating receptor on myeloid cells 1 (TARM-1) is a novel leukocyte receptor expressed in neutrophils and macrophages. It plays an important role in proinflammatory response in acute bacterial infection, but its immunomodulatory effects on chronic Mycobacterium tuberculosis infections remain unclear. TARM-1 expression was significantly upregulated on CD14high monocytes from patients with active pulmonary tuberculosis (TB) as compared that on cells from patients with latent TB or from healthy control subjects. Small interfering RNA knockdown of TARM-1 reduced expression levels of proinflammatory cytokines IL-12, IL-18, IL-1ß, and IL-8 in M. tuberculosis-infected macrophages, as well as that of HLA-DR and costimulatory molecules CD83, CD86, and CD40. Moreover, TARM-1 enhanced phagocytosis and intracellular killing of M. tuberculosis through upregulating reactive oxygen species. In an in vitro monocyte and T cell coculture system, blockade of TARM-1 activity by TARM-1 blocking peptide suppressed CD4+ T cell activation and proliferation. Finally, administration of TARM-1 blocking peptide in a mouse model of M. tuberculosis infection increased bacterial load and lung pathology, which was associated with decreased macrophage activation and IFN-γ production by T cell. Taken together, these results, to our knowledge, demonstrate a novel immune protective role of TARM-1 in M. tuberculosis infection and provide a potential therapeutic target for TB disease.


Assuntos
Macrófagos/imunologia , Receptores Imunológicos/imunologia , Células Th1/imunologia , Tuberculose/imunologia , Adulto , Estudos de Coortes , Feminino , Humanos , Ativação de Macrófagos/imunologia , Masculino , Receptores Imunológicos/genética
5.
Artigo em Inglês | MEDLINE | ID: mdl-29606863

RESUMO

Purpose: This study aimed to investigate the impact of cigarette smoke exposure upon CD40-CD40L ligation between bone marrow-derived dendritic cells (BMDCs)and CD4+T cells, and to examine the effects of cigarette smoke exposure upon differentiation of CD4+T cells toward Th17 cells through blockade of CD40-CD40L pathway in mice. Methods: The study was processed in vivo and in vitro. In vivo, Th17 cells, CD40, interleukin (IL)-17A, and IL-27 in the lung tissues were quantified and compared between mice with and without cigarette smoke exposure. In vitro, Th17 cells, IL-17A, and IL-27 yielded by multiple cell cultivations in which BMDCs from mice with or without cigarette smoke exposure were fostered with CD4+ T cells from healthy mice spleens in the presence of antagonistic CD40 antibody and/or cigarette smoke extract (CSE) were quantified and compared. The flow cytometry was used to detect expressions of Th17 cells and CD40, and the liquid chip was used to detect levels of IL-17A and IL-27. Results: Both in vivo exposed to cigarette smoke and in vitro to CSE, CD40 expressions noticeably escalated on the surfaces of BMDCs. The presence of Th17 cells, IL-17A, and IL-27 in the lung tissues prominently increased in mice exposed to cigarette smoke. The in vitro culture of CD4+ T cells and BMDCs significantly enhanced the differentiation of CD4+ T cells toward Th17 cells and secretions of IL-17A and IL-27 in the case that BMDCs were produced from mice exposed to cigarette smoke or the culture occurred in the presence of CSE. Usage of antagonistic CD40 antibody evidently reduced the number of Th17 cells, IL-17A, and IL-27 that increased due to cigarette smoke exposure. Conclusion: The CD40-CD40L ligation is associated with the quantities of Th17 cells and relevant cytokines in the context of cigarette smoke exposure. Reducing the number of Th17 cells via the usage of antagonistic CD40 antibody can be an inspiration for pursuing a novel therapeutic target for immune inflammation in COPD.


Assuntos
Antígenos CD40/imunologia , Ligante de CD40/imunologia , Diferenciação Celular , Fumar Cigarros/efeitos adversos , Pulmão/imunologia , Ativação Linfocitária , Fumaça/efeitos adversos , Células Th17/imunologia , Animais , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Comunicação Celular , Células Cultivadas , Fumar Cigarros/imunologia , Fumar Cigarros/metabolismo , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Fenótipo , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Células Th17/metabolismo
6.
Clin Immunol ; 195: 107-118, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29127016

RESUMO

Plasmacytoid dendritic cells (pDCs) are key cells bridging the innate with adaptive immunity. However, the phenotypic characteristics of circulating pDCs and its role in smoking related-Chronic Obstructive Pulmonary Disease (COPD) remain largely unknown. The aim of this study was analyzed the phenotype of circulating pDCs and the expression of IFN-γ producing CD8+T cells and IL-17-producing CD8+T cells in patients with COPD by using multi-colour flow cytometry. The cytokine profiles in peripheral blood from all subjects were measured by ELISA. The influence of cigarette smoke on pDCs was evaluated in an experimental mouse model of emphysema. Circulating pDCs in patients with COPD and in mice exposed to cigarette smoke expressed high levels of co-stimulatory molecules CD40 or CD86 accompanied by exaggerated IFN-γ producing CD8+T cells and IL-17-producing CD8+T cells. In vitro, cigarette smoke directly promoted pDCs maturation and release of IFN-α, IL-6 and IL-12, subsequently inducing differentiation of IFN-γ producing CD8+T cells and IL-17-producing CD8+T cells from mouse naïve CD8+T cells. These data suggested that circulating pDCs display an enhanced activation phenotype in patients with COPD and in experimental smoking mouse model of emphysema, which might contribute to exaggerated IFN-γ producing CD8+T and IL-17-producing CD8+T cell-mediated immune responses.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Enfisema Pulmonar/imunologia , Idoso , Animais , Circulação Sanguínea , Diferenciação Celular , Células Cultivadas , Fumar Cigarros/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Enfisema Pulmonar/induzido quimicamente
7.
Am J Physiol Lung Cell Mol Physiol ; 311(3): L581-9, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27448664

RESUMO

Dendritic cells and CD8(+) T cells participate in the pathology of chronic obstructive pulmonary disease, including emphysema, but little is known of the involvement of the CD40/CD40L pathway. We investigated the role of the CD40/CD40L pathway in Tc1 cell differentiation induced by dendritic cells in a mouse model of emphysema, and in vitro. C57BL/6J wild-type and CD40(-/-) mice were exposed to cigarette smoke (CS) or not (control), for 24 wk. In vitro experiments involved wild-type and CD40(-/-) dendritic cells treated with CS extract (CSE) or not. Compared with the control groups, the CS mice (both wild type and CD40(-/-)) had a greater percentage of lung dendritic cells and higher levels of major histocompatability complex (MHC) class I molecules and costimulatory molecules CD40 and CD80. Relative to the CS CD40(-/-) mice, the CS wild type showed greater signs of lung damage and Tc1 cell differentiation. In vitro, the CSE-treated wild-type cells evidenced more cytokine release (IL-12/p70) and Tc1 cell differentiation than did the CSE-treated CD40(-/-) cells. Exposure to cigarette smoke increases the percentage of lung dendritic cells and promotes Tc1 cell differentiation via the CD40/CD40L pathway. Blocking the CD40/CD40L pathway may suppress development of emphysema in mice exposed to cigarette smoke.


Assuntos
Antígenos CD40/fisiologia , Ligante de CD40/fisiologia , Células Dendríticas/fisiologia , Enfisema Pulmonar/imunologia , Fumaça/efeitos adversos , Animais , Linfócitos T CD8-Positivos , Diferenciação Celular , Células Cultivadas , Citocinas/biossíntese , Citocinas/genética , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Contagem de Linfócitos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Transdução de Sinais , Fumar/efeitos adversos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Nicotiana/efeitos adversos
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