Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int Immunol ; 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38573198

RESUMO

Efficient induction of humoral immune responses depends on orchestrated migration of B cells within lymphoid organs, which is governed by G protein-coupled receptors (GPCRs) responding to chemoattractants, represented by chemokines. After ligand binding, GPCRs are phosphorylated by different GPCR kinases (GRKs) at distinct sites on the receptor C termini, which dictates functional outcomes of ß-arrestin-mediated signaling, ranging from receptor inactivation to effector molecule activation. However, the molecular mechanisms by which individual GRKs are selectively targeted to GPCRs have been poorly understood. Our recent study revealed that a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and 8 (COMMD3/8 complex) functions as an adaptor that recruits a specific GRK to chemoattractant receptors and plays an important role in the control of B cell migration during humoral immune responses. In this review, we summarize the current understanding of chemoattractant receptor signaling in the context of humoral immunity and discuss the potential of the COMMD3/8 complex as a therapeutic target for autoimmune diseases.

2.
Brain Behav Immun ; 113: 66-82, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37369341

RESUMO

Stress-induced ß2-adrenergic receptor (ß2AR) activation in B cells increases IgG secretion; however, the impact of this activation on antibody affinity and the underlying mechanisms remains unclear. In the current study, we demonstrate that stress in mice following ovalbumin (OVA) or SARS-CoV-2 RBD immunization significantly increases both serum and surface-expressed IgG binding to the immunogen, while concurrently reducing surface IgG expression and B cell clonal expansion. These effects were abolished by pharmacological ß2AR blocking or when the experiments were conducted in ß2AR -/- mice. In the second part of our study, we used single B cell sorting to characterize the monoclonal antibodies (mAbs) generated following ß2AR activation in cultured RBD-stimulated B cells from convalescent SARS-CoV-2 donors. Ex vivo ß2AR activation increased the affinities of the produced anti-RBD mAbs by 100-fold compared to mAbs produced by the same donor control cultures. Consistent with the mouse experiments, ß2AR activation reduced both surface IgG levels and the frequency of expanded clones. mRNA sequencing revealed a ß2AR-dependent upregulation of the PI3K pathway and B cell receptor (BCR) signaling through AKT phosphorylation, as well as an increased B cell motility. Overall, our study demonstrates that stress-mediated ß2AR activation drives changes in B cells associated with BCR activation and higher affinity antibodies.


Assuntos
Adrenérgicos , COVID-19 , Camundongos , Animais , Fosfatidilinositol 3-Quinases , SARS-CoV-2/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Imunoglobulina G
3.
Sci Immunol ; 8(81): eadc9324, 2023 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-37000855

RESUMO

Celastrol, a bioactive molecule extracted from the Tripterygium wilfordii plant, has been shown to exhibit anti-inflammatory properties. However, its mechanism of action has not been fully elucidated. Here, we show that celastrol suppresses humoral immune responses and autoimmunity by disabling a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and COMMD8 (COMMD3/8 complex), a signaling adaptor for chemoattractant receptors. Having demonstrated the involvement of the COMMD3/8 complex in a mouse model of rheumatoid arthritis, we identified celastrol as a compound that covalently bound to and dissociated the COMMD3/8 complex. Celastrol inhibited B cell migration, reduced antibody responses, and blocked arthritis progression, recapitulating deficiency of the COMMD3/8 complex. These effects of celastrol were abolished in mice expressing a celastrol-resistant mutant of the COMMD3/8 complex. These findings establish that celastrol exerts immunosuppressive activity by targeting the COMMD3/8 complex. Our study suggests that the COMMD3/8 complex is a potentially druggable target in autoimmune diseases and points to celastrol as a lead pharmacologic candidate in this capacity.


Assuntos
Doenças Autoimunes , Imunidade Humoral , Camundongos , Animais , Autoimunidade , Triterpenos Pentacíclicos
4.
Int Immunol ; 33(6): 327-335, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33751050

RESUMO

Cell migration is a cardinal feature of the immune system. Immune cell trafficking is orchestrated principally by chemokines and adhesion molecules, which guide the cells to the right place and at the right time to efficiently induce immune responses. Recent studies have demonstrated that signals from other organ systems influence the expression of and responsiveness to these guidance cues and consequentially immune cell migration. Neuronal inputs control entry and exit of immune cells to and from lymphoid and non-lymphoid tissues. The circadian clock helps establish diurnal variations in immune cell distribution among tissues. Nutritional status also alters immune cell homing to the bone marrow. In this review, we summarize the current knowledge about inter-organ control of immune cell trafficking and discuss the physiological and pathological significance of these mechanisms.


Assuntos
Transporte Biológico/imunologia , Sistema Imunitário/imunologia , Animais , Movimento Celular/imunologia , Quimiocinas/imunologia , Humanos
5.
J Exp Med ; 216(7): 1630-1647, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31088898

RESUMO

Lymphocyte migration is mediated by G protein-coupled receptors (GPCRs) that respond to chemoattractive molecules. After their activation, GPCRs are phosphorylated by different GPCR kinases (GRKs), which produces distinct functional outcomes through ß-arrestins. However, the molecular machinery that targets individual GRKs to activated GPCRs remains elusive. Here, we identified a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and COMMD8 (COMMD3/8 complex) as an adaptor that selectively recruits a specific GRK to chemoattractant receptors and promotes lymphocyte chemotaxis. COMMD8, whose stability depended on COMMD3, was recruited to multiple chemoattractant receptors. Deficiency of COMMD8 or COMMD3 impaired B cell migration and humoral immune responses. Using CXC-chemokine receptor 4 (CXCR4) as a model, we demonstrated that the COMMD3/8 complex selectively recruited GRK6 and induced GRK6-mediated phosphorylation of the receptor and activation of ß-arrestin-mediated signaling. Thus, the COMMD3/8 complex is a specificity determinant of GRK targeting to GPCRs and represents a point of regulation for immune responses.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Quinases de Receptores Acoplados a Proteína G/metabolismo , Proteínas/metabolismo , Receptores de Formil Peptídeo/metabolismo , Animais , Linfócitos B/metabolismo , Quimiotaxia de Leucócito , Citometria de Fluxo , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Células HEK293 , Humanos , Imunidade Humoral , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Fosforilação , Receptores CXCR4/metabolismo , Técnicas do Sistema de Duplo-Híbrido , beta-Arrestinas/metabolismo
6.
Neurochem Int ; 130: 104320, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30342959

RESUMO

Since the beginning of the last century, substantial evidence has suggested that various aspects of the immune system are influenced by the activity of the nervous system. However, the cellular and molecular basis for the neural control of immune responses has emerged only in the past decade. Recent studies have shown that adrenergic nerves control trafficking of immune cells through cell-type-specific mechanisms. Activation of the ß2-adrenergic receptor expressed on lymphocytes enhances signals mediated by a particular set of chemokine receptors, and consequently inhibits their exit from lymph nodes. This mechanism is involved in the diurnal variation of adaptive immune responses and the progression of inflammatory diseases. In the present review, we focus on the role of adrenergic nerves in the control of lymphocyte trafficking and adaptive immune responses in physiological and pathological conditions.


Assuntos
Imunidade Adaptativa/fisiologia , Neurônios Adrenérgicos/metabolismo , Linfócitos/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Neurônios Adrenérgicos/imunologia , Animais , Ritmo Circadiano/fisiologia , Humanos , Linfócitos/imunologia , Transporte Proteico/fisiologia , Receptores Adrenérgicos beta 2/imunologia
8.
J Exp Med ; 213(12): 2567-2574, 2016 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-27799619

RESUMO

Various aspects of the immune system display circadian rhythms. Although lymphocyte trafficking has been suggested to show diurnal variations, the mechanisms and influences on immune responses are unclear. Here, we show in mice that inputs from adrenergic nerves contribute to the diurnal variation of lymphocyte recirculation through lymph nodes (LNs), which is reflected in the magnitude of the adaptive immune response. Neural inputs to ß2-adrenergic receptors (ß2ARs) expressed on lymphocytes reduced the frequency of lymphocyte egress from LNs at night, which was accompanied by an increase of lymphocyte numbers in LNs. Immunization during the period of lymphocyte accumulation in LNs enhanced antibody responses. The diurnal variation of the humoral immune response was dependent on ß2AR-mediated neural signals and was diminished when lymphocyte recirculation through LNs was stopped. This study reveals the physiological role of adrenergic control of lymphocyte trafficking in adaptive immunity and establishes a novel mechanism that generates diurnal rhythmicity in the immune system.


Assuntos
Imunidade Adaptativa/imunologia , Ritmo Circadiano/imunologia , Linfonodos/imunologia , Linfócitos/imunologia , Receptores Adrenérgicos beta 2/metabolismo , Animais , Imunidade Humoral , Contagem de Linfócitos , Linfócitos/citologia , Camundongos Endogâmicos C57BL
9.
J Exp Med ; 211(13): 2583-98, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25422496

RESUMO

Lymphocyte recirculation through secondary lymphoid organs is essential for immunosurveillance and lymphocyte effector functions. Here, we show that signals through ß2-adrenergic receptors (ß2ARs) expressed on lymphocytes are involved in the control of lymphocyte dynamics by altering the responsiveness of chemoattractant receptors. Agonist stimulation of lymphocyte ß2ARs inhibited egress of lymphocytes from lymph nodes (LNs) and rapidly produced lymphopenia in mice. Physiological inputs from adrenergic nerves contributed to retention of lymphocytes within LNs and homeostasis of their distribution among lymphoid tissues. ß2ARs physically interacted with CCR7 and CXCR4, chemokine receptors promoting lymphocyte retention in LNs. Activation of ß2ARs enhanced retention-promoting signals through CCR7 and CXCR4, and consequently inhibited lymphocyte egress from LNs. In models of T cell-mediated inflammatory diseases, ß2AR-mediated signals inhibited LN egress of antigen-primed T cells and reduced their recruitment into peripheral tissues. Thus, this study reveals a novel mechanism for controlling lymphocyte trafficking and provides additional insights into immune regulation by the nervous system.


Assuntos
Linfonodos/citologia , Linfonodos/imunologia , Linfócitos/imunologia , Receptores Adrenérgicos beta 2/metabolismo , Animais , Antígenos/imunologia , Inflamação/imunologia , Inflamação/patologia , Linfopenia/imunologia , Linfopenia/patologia , Camundongos Endogâmicos C57BL , Ligação Proteica , Receptores CCR7/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais/imunologia
10.
Am J Kidney Dis ; 48(6): 986-9, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17162154

RESUMO

A patient who underwent living donor kidney transplantation was infected with Epstein-Barr virus (EBV) that resulted in persistent EBV infection and EBV-associated chronic hepatitis, determined by abnormally elevated anti-EBV antibody titers and high frequency of EBV-infected B lymphocytes. Despite decreases in immunosuppressant doses, persistent EBV infection and chronic hepatitis persisted for several years. Therapy using anti-CD20 monoclonal antibody (rituximab) virtually eliminated peripheral B lymphocytes and EBV-encoded small RNA 1 (EBER-1)-positive cells. Moreover, hepatic enzyme levels normalized and histological findings indicated marked improvement in hepatic inflammation. Although peripheral CD20(+) B lymphocyte and EBER-1-positive cell levels began to increase 4 months after the end of therapy, the number of EBER-1-positive cells remained very low, and liver function test results remained within normal ranges. The present case illustrates the significance of early diagnosis, monitoring of viral load, and vigorous management of EBV-related disorders associated with organ transplantation.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Hepatite Crônica/tratamento farmacológico , Hepatite Viral Humana/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Transplante de Rim , Complicações Pós-Operatórias/tratamento farmacológico , Adolescente , Anticorpos Monoclonais Murinos , Infecções por Vírus Epstein-Barr/patologia , Feminino , Hepatite Crônica/patologia , Hepatite Viral Humana/patologia , Humanos , Fígado/patologia , Doadores Vivos , Nefrite Intersticial/cirurgia , Rituximab
11.
Pediatr Res ; 58(4): 666-71, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16189191

RESUMO

To clarify the patterns of heme oxygenase-1 (HO-1) production within the human kidney, we examined HO-1 mRNA expression in various renal diseases and compared the patterns with those of HO-1 protein expression and these data with the clinical features. The degrees of hematuria and proteinuria and the levels of urinary N-acetyl-beta-D-glucosaminidase (NAG), beta(2)-microglobulin (beta(2)-mg), and creatinine were determined. In situ hybridization and immunohistochemical studies were performed to evaluate HO-1 expression. HO-1 mRNA was detectable within tubular, glomerular, and Bowman's epithelial cells and infiltrating macrophages. Within the proximal tubuli, there was a correlation between expression of HO-1 protein and mRNA, but the intensity of HO-1 mRNA expression was much less than expected from the levels of protein. In contrast, both HO-1 protein and mRNA were expressed at significant levels within distal tubuli. Furthermore, there was no correlation with both expressions within distal tubuli. HO-1 mRNA expression within tubular, glomerular, and Bowman's epithelial cells tended to be more intense with greater degrees of proteinuria. However, there was little correlation between the intensity of HO-1 mRNA expression and the degree of hematuria, NAG, and beta(2)-mg. HO-1 plays important roles in maintaining renal functions by protecting renal epithelial cells from glomerular proteinuria, which can become a cause of oxidative stress. Furthermore, from the different expression pattern of HO-1 gene between within the proximal tubuli and within the distal tubuli, renal expression of HO-1 is regulated in a segment-specific manner, with HO-1 thereby playing distinct roles in different segments of the nephron to maintain renal functions.


Assuntos
Células Epiteliais/citologia , Regulação Enzimológica da Expressão Gênica , Heme Oxigenase-1/metabolismo , Rim/metabolismo , Proteinúria/metabolismo , Acetilglucosaminidase/química , Adolescente , Animais , Criança , Pré-Escolar , Creatinina/química , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Glomérulos Renais/metabolismo , Túbulos Renais/metabolismo , Masculino , Néfrons/metabolismo , Estresse Oxidativo , RNA Mensageiro/metabolismo , Ratos , Microglobulina beta-2/metabolismo
12.
Kidney Int ; 64(4): 1302-9, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12969148

RESUMO

BACKGROUND: The renal pathology of human heme oxygenase (HO)-1 deficiency is characterized by advanced tubulointerstitial injury, whereas the glomerular structures are affected little. These facts suggest that the renal tubuli are dependent on intrinsic HO-1 production for their survival under oxidative stresses. METHODS: We compared the patterns of HO-1 expression by primary cultured human mesangial cells (HMCs) and renal proximal tubular epithelial cells (HRPTECs) in vitro. Furthermore, the cytoprotective roles of HO-1 induced in these cells were evaluated by stress-induced cytotoxicity assays. HO-1 expressions in HRPTECs and HMCs were evaluated by immunoblotting, and by reverse transcriptase (RT) and/or real time polymerase chain reaction (PCR). RESULTS: In HRPTECs, both HO-1 mRNA expression and protein production peaked at around 12 h and persisted until 24 h after hemin stimulation. In contrast, HO-1 mRNA expression and protein production by HMCs peaked at 4 h and 6 h respectively, and the levels declined rapidly, being undetectable at 24 h. The peak level of HO-1 expression was significantly higher in HRPTECs than in HMCs. Oxidative stress-induced cell injury in HRPTECs was significantly reduced when HO-1 production had been induced prior to the culture. In contrast, HO-1 induction had little cytoprotective effect on HMCs. Tin protoporphyrin (SnPP), an inhibitor of HO function, significantly reversed the cytoprotection by HO-1. CONCLUSION: These data suggest that HRPTECs are more susceptible to oxidative stress and are significantly more dependent on HO-1 for protection against noxious stimuli than HMCs. Collectively, these results indicate that HO-1 is an important protective factor for kidney tissue, in particular, renal tubular epithelial cells.


Assuntos
Citoproteção , Heme Oxigenase (Desciclizante)/metabolismo , Túbulos Renais Proximais/enzimologia , Túbulos Renais Proximais/patologia , Estresse Oxidativo , Células Cultivadas , Citoproteção/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Mesângio Glomerular/enzimologia , Mesângio Glomerular/patologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase-1 , Hemina/farmacologia , Humanos , Proteínas de Membrana , Metaloporfirinas/farmacologia , Protoporfirinas/farmacologia , RNA Mensageiro/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...