Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS One ; 18(1): e0280590, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662882

RESUMO

C-C motif chemokine receptor-like 2 (CCRL2) is a non-signaling 7 transmembrane receptor that binds chemotactic ligands to shape leukocyte recruitment to sites of inflammation. However, there is a lack of consensus on the ligands that directly bind CCRL2 or their functional impact. Studies with CCRL2 knockout mice have demonstrated that neutrophils have impaired degranulation and migration in response to CXCL8, where the underlying molecular mechanism is proposed to be due to the formation of CCRL2 heterodimers with the chemokine receptor CXCR2. Herein, we characterized the ligands that bind directly to CCRL2 and interrogated the impact of CCRL2 neutralization on CXCL8 signaling in neutrophils using pharmacological antibody tools. Using flow cytometry and Surface Plasmon Resonance microscopy (SPRm) cell binding experiments, we confirmed that chemerin, but not previously reported C-C chemokines, binds CCRL2. Furthermore, we identified human and mouse CCRL2 antibodies that neutralized chemerin binding to CCRL2. Unexpectedly, we found that neutralization of CCRL2 with these antibodies did not attenuate CXCL8-induced human neutrophil degranulation nor CXCL8-induced murine neutrophil recruitment to the peritoneum. Based on the observed differences in modulating CCRL2 function with neutralizing antibodies compared to the reported CCRL2 deficient murine models, we hypothesize that the ligand binding function of CCRL2 is dispensable for CXCL8 signaling in neutrophils. Finally, extensive profiling of CCRL2 expression on peripheral blood leukocytes revealed monocytes, dendritic cells (DC), and subpopulations of natural killer T (NKT) cells as additional targets, highlighting potential roles for CCRL2 in human cell types beyond neutrophils that warrants future investigation.


Assuntos
Ativação de Neutrófilo , Receptores CCR , Humanos , Animais , Camundongos , Receptores CCR/metabolismo , Anticorpos Neutralizantes/farmacologia , Ligantes , Transdução de Sinais , Interleucina-8 , Neutrófilos/metabolismo
2.
Elife ; 92020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33200983

RESUMO

The lymphatic vasculature is involved in the pathogenesis of acute cardiac injuries, but little is known about its role in chronic cardiac dysfunction. Here, we demonstrate that angiotensin II infusion induced cardiac inflammation and fibrosis at 1 week and caused cardiac dysfunction and impaired lymphatic transport at 6 weeks in mice, while co-administration of VEGFCc156s improved these parameters. To identify novel mechanisms underlying this protection, RNA sequencing analysis in distinct cell populations revealed that VEGFCc156s specifically modulated angiotensin II-induced inflammatory responses in cardiac and peripheral lymphatic endothelial cells. Furthermore, telemetry studies showed that while angiotensin II increased blood pressure acutely in all animals, VEGFCc156s-treated animals displayed a delayed systemic reduction in blood pressure independent of alterations in angiotensin II-mediated aortic stiffness. Overall, these results demonstrate that VEGFCc156s had a multifaceted therapeutic effect to prevent angiotensin II-induced cardiac dysfunction by improving cardiac lymphatic function, alleviating fibrosis and inflammation, and ameliorating hypertension.


Assuntos
Células Endoteliais/metabolismo , Cardiopatias/metabolismo , Miocárdio/metabolismo , Fator C de Crescimento do Endotélio Vascular/farmacologia , Angiotensina II/toxicidade , Animais , Biomarcadores , Técnicas de Introdução de Genes , Estudo de Associação Genômica Ampla , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Hipertensão/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Análise de Sequência de RNA , Proteínas Supressoras de Tumor/metabolismo , Fator C de Crescimento do Endotélio Vascular/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...