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1.
Cell ; 172(5): 1050-1062.e14, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474906

RESUMO

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.


Assuntos
Meduloblastoma/irrigação sanguínea , Meduloblastoma/patologia , Neoplasias Meníngeas/irrigação sanguínea , Neoplasias Meníngeas/secundário , Aloenxertos , Animais , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Cromossomos Humanos Par 10/genética , Feminino , Humanos , Masculino , Meduloblastoma/genética , Camundongos SCID , Células Neoplásicas Circulantes , Parabiose
2.
Nat Immunol ; 17(11): 1263-1272, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27668800

RESUMO

Regions of the normal arterial intima predisposed to atherosclerosis are sites of ongoing monocyte trafficking and also contain resident myeloid cells with features of dendritic cells. However, the pathophysiological roles of these cells are poorly understood. Here we found that intimal myeloid cells underwent reverse transendothelial migration (RTM) into the arterial circulation after systemic stimulation of pattern-recognition receptors (PRRs). This process was dependent on expression of the chemokine receptor CCR7 and its ligand CCL19 by intimal myeloid cells. In mice infected with the intracellular pathogen Chlamydia muridarum, blood monocytes disseminated infection to the intima. Subsequent CCL19-CCR7-dependent RTM was critical for the clearance of intimal C. muridarum. This process was inhibited by hypercholesterolemia. Thus, RTM protects the normal arterial intima, and compromised RTM during atherogenesis might contribute to the intracellular retention of pathogens in atherosclerotic lesions.


Assuntos
Quimiocina CCL19/metabolismo , Chlamydia muridarum/imunologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores CCR7/metabolismo , Migração Transendotelial e Transepitelial , Túnica Íntima/imunologia , Túnica Íntima/metabolismo , Animais , Antígeno CD11c/metabolismo , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/metabolismo , Infecções por Chlamydia/virologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/microbiologia , RNA Mensageiro/genética , Transdução de Sinais , Receptores Toll-Like/metabolismo , Túnica Íntima/microbiologia
3.
Nat Immunol ; 17(2): 159-68, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26642357

RESUMO

Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1(+) precursors and postnatally from bone marrow-derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche.


Assuntos
Autorrenovação Celular , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Receptores de Quimiocinas/metabolismo , Animais , Receptor 1 de Quimiocina CX3C , Sobrevivência Celular , Quimiocina CX3CL1/metabolismo , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Imunofenotipagem , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Transgênicos , Fenótipo , Ligação Proteica , Nicho de Células-Tronco , Transcriptoma
6.
Cell Rep ; 27(8): 2304-2312.e6, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31116977

RESUMO

Mechanisms that govern transcriptional regulation of inflammation in atherosclerosis remain largely unknown. Here, we identify the nuclear transcription factor c-Myb as an important mediator of atherosclerotic disease in mice. Atherosclerosis-prone animals fed a diet high in cholesterol exhibit increased levels of c-Myb in the bone marrow. Use of mice that either harbor a c-Myb hypomorphic allele or where c-Myb has been preferentially deleted in B cell lineages revealed that c-Myb potentiates atherosclerosis directly through its effects on B lymphocytes. Reduced c-Myb activity prevents the expansion of atherogenic B2 cells yet associates with increased numbers of IgM-producing antibody-secreting cells (IgM-ASCs) and elevated levels of atheroprotective oxidized low-density lipoprotein (OxLDL)-specific IgM antibodies. Transcriptional profiling revealed that c-Myb has a limited effect on B cell function but is integral in maintaining B cell progenitor populations in the bone marrow. Thus, targeted disruption of c-Myb beneficially modulates the complex biology of B cells in cardiovascular disease.


Assuntos
Células Produtoras de Anticorpos/imunologia , Aterosclerose/genética , Aterosclerose/imunologia , Imunoglobulina M/metabolismo , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/imunologia , Animais , Células Produtoras de Anticorpos/metabolismo , Aterosclerose/patologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Genes myb , Masculino , Camundongos
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