Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 356
Filtrar
1.
Nat Med ; 25(12): 1839-1842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768065

RESUMO

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.


Assuntos
Quinase do Linfoma Anaplásico/genética , Histiocitose/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adolescente , Adulto , Aminopiridinas/farmacologia , Benzotiazóis/farmacologia , Criança , Pré-Escolar , Feminino , Genoma Humano , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histiocitose/tratamento farmacológico , Histiocitose/patologia , Humanos , Lactente , Masculino , Mutação , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma , Adulto Jovem
2.
Nat Commun ; 10(1): 3758, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434879

RESUMO

Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aß deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.


Assuntos
Doença de Alzheimer/metabolismo , Microglia/metabolismo , Compostos Orgânicos/farmacologia , Placa Amiloide/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Doença de Alzheimer/genética , Animais , Comportamento Animal , Encéfalo/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipocampo/metabolismo , Humanos , Memória , Camundongos , Camundongos Transgênicos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Transcriptoma
3.
Nat Commun ; 10(1): 3215, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324781

RESUMO

The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r-/- rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.


Assuntos
Genes fms/genética , Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Deleção de Sequência , Animais , Sequência de Bases , Diferenciação Celular , Proliferação de Células , Modelos Animais de Doenças , Células-Tronco Embrionárias/patologia , Fator de Crescimento Epidérmico , Feminino , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Macrófagos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Monócitos/metabolismo , Fagocitose , Células RAW 264.7 , Sequências Reguladoras de Ácido Nucleico/genética
5.
Int J Lab Hematol ; 41(4): 572-577, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31149782

RESUMO

INTRODUCTION: The formation of neutralizing antibodies (FVIII inhibitors) in haemophilia A patients is an immune response to the deficient factor. This process is multifactorial and includes environmental and genetic factors. Some genetic markers that play a decisive role in the immune response have been identified as risk factors for inhibitor development. OBJECTIVE: Our aim was to investigate the association between polymorphisms in several genes involved in the regulation of the immune response and inhibitor development in patients with haemophilia A in North China. METHODS: We analysed eight SNPs (MAPK9 rs4147385, CSF1R rs17725712, CD44 rs927335, STAT4 rs7574865, IKZF1 rs4917014, ETS1 rs6590330, BANK1 rs17266594 and rs10516487) by Snapshot SNP genotyping assays in 100 haemophilia A patients, including 29 with inhibitors and 71 without inhibitors. RESULTS: Our results demonstrated that the rs17725712 A allele and the AA homozygous genotype of CSF1R were more frequent in patients with inhibitors. The rs4147385 G allele in MAPK9 was also more frequent in the inhibitor cohort. CONCLUSION: We confirmed an association of CSF1R rs17725712 and MAPK9 rs4147385 with inhibitor development in haemophilia A patients in North China.


Assuntos
Alelos , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIII/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/genética , Polimorfismo de Nucleotídeo Único , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Anticorpos Neutralizantes/sangue , Grupo com Ancestrais do Continente Asiático , Autoanticorpos/sangue , China , Fator VIII/genética , Fator VIII/metabolismo , Hemofilia A/sangue , Hemofilia A/genética , Humanos , Masculino
6.
Medicine (Baltimore) ; 98(22): e15802, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31145310

RESUMO

RATIONALE: Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a rare disease with white matter lesions of the central nervous system, and it usually has autosomal dominant inheritance. Its pathogenesis and causes are complex, and it has obvious clinical and genetic heterogeneities; also, it is classed as a neurodegenerative disease. PATIENT CONCERNS: In preliminary clinical work, we identified a family with rapid progressive dementia. DIAGNOSIS: Within this family, all patients had a CSF1R gene c.2696delA mutation (a deletion mutation), and head magnetic resonance imaging showed extensive white matter lesions. We diagnosed these patients with HDLS. INTERVENTIONS: The proband was given hormonal treatments and immunoglobulin therapy, and his dementia symptoms have been relieved to a certain extent. OUTCOMES: After treatment, the symptoms of dementia were still progressively aggravated. However, the mutation site has not previously been reported. LESSONS: This newly discovered mutation site may provide a new basis for the genetic diagnosis of HDLS disease in clinical work.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Humanos , Masculino , Mutação , Linhagem
7.
Am J Hum Genet ; 104(5): 936-947, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982608

RESUMO

Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia. The second individual had a homozygous missense mutation (c.1929C>A [p.His643Gln]) and presented with developmental delay and epilepsy in childhood. We analyzed a zebrafish model (csf1rDM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor. CUX1+ neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1+ neurons. Since a large fraction of CUX1+ neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1+ neurons. Our results suggest that CSF1R is required for human brain development and establish the csf1rDM fish as a model for microgliopathies. In addition, our results exemplify an under-recognized form of phenotypic expansion, in which genes associated with well-recognized, dominant conditions produce different phenotypes when biallelically mutated.


Assuntos
Anormalidades Congênitas/etiologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Microglia/patologia , Mutação , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Animais , Criança , Anormalidades Congênitas/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Homozigoto , Humanos , Lactente , Recém-Nascido , Microglia/metabolismo , Linhagem , Fenótipo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adulto Jovem , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
8.
Am J Hum Genet ; 104(5): 925-935, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982609

RESUMO

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.


Assuntos
Encéfalo/anormalidades , Leucoencefalopatias/etiologia , Mutação , Osteocondrodisplasias/etiologia , Osteosclerose/etiologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adolescente , Adulto , Alelos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Pré-Escolar , Feminino , Humanos , Leucoencefalopatias/patologia , Masculino , Camundongos , Camundongos Knockout , Osteocondrodisplasias/patologia , Osteosclerose/patologia , Fenótipo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/fisiologia , Adulto Jovem
9.
Nat Commun ; 10(1): 1935, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028249

RESUMO

Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are also found in the nucleus, as either intracellular domains or full length proteins. However, their potential nuclear functions remain poorly understood. Here we find that a fraction of full length Colony Stimulating Factor-1 Receptor (CSF-1R), an RTK involved in monocyte/macrophage generation, migrates to the nucleus upon CSF-1 stimulation in human primary monocytes. Chromatin-immunoprecipitation identifies the preferential recruitment of CSF-1R to intergenic regions, where it co-localizes with H3K4me1 and interacts with the transcription factor EGR1. When monocytes are differentiated into macrophages with CSF-1, CSF-1R is redirected to transcription starting sites, colocalizes with H3K4me3, and interacts with ELK and YY1 transcription factors. CSF-1R expression and chromatin recruitment is modulated by small molecule CSF-1R inhibitors and altered in monocytes from chronic myelomonocytic leukemia patients. Unraveling this dynamic non-canonical CSF-1R function suggests new avenues to explore the poorly understood functions of this receptor and its ligands.


Assuntos
Regulação da Expressão Gênica , Leucemia Mielomonocítica Crônica/genética , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/efeitos dos fármacos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Sistemas CRISPR-Cas , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cromatina/química , Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Corantes Fluorescentes/química , Edição de Genes , Células HEK293 , Histonas/genética , Histonas/metabolismo , Humanos , Leucemia Mielomonocítica Crônica/metabolismo , Leucemia Mielomonocítica Crônica/patologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Maleimidas/química , Cultura Primária de Células , Ligação Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transdução de Sinais , Células THP-1 , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismo , Proteínas Elk-1 do Domínio ets/genética , Proteínas Elk-1 do Domínio ets/metabolismo
10.
Iran J Kidney Dis ; 13(2): 87-97, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30988245

RESUMO

INTRODUCTION: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus involving damage to the capillaries in the glomerulus. This study aimed to explore key genes and signaling pathways participate in the progression of DN. METHODS: Two gene expression profile datasets GSE1009 and GSE30528 downloaded from Gene Expression Omnibus (GEO) were used to analyze the differentially expressed genes (DEGs) between DN samples and controls. Coupled two-way clustering (CTWC) and correspondence analysis were performed to explore the potential functions of DEGs. Then, Gene Ontology (GO) terms and pathways associated with DEGs were identified, followed by constructing of the co-expressed gene network and module. Ultimately, the regulatory network based on the DEGs, miRNAs and transcription factors (TFs) was established. RESULTS: Total 283 common DEGs were identified from the two datasets, including 219 down-regulated ones (bone morphogenetic protein 7 (BMP7), decay accelerating factor (CD55) and coagulation Factor V (F5) etc.) and 64 up-regulated ones (inhibin beta c subunit (INHBC) and colony stimulating factor 1 receptor (CSF1R) etc.). The miRNA-TF regulatory network was established with three miRNAs, 8 TFs and 58 DEGs. Besides, three significant pathways including cytokine-cytokine receptor interaction, complement and coagulation cascades and TGF-beta signaling pathways were identified. CONCLUSION: BMP7, CD55, CSF1R, INHBC and F5 are likely to take crucial roles in the pathogenesis of DN.


Assuntos
Nefropatias Diabéticas/genética , Transdução de Sinais/genética , Proteína Morfogenética Óssea 7/genética , Antígeno CD56/genética , Nefropatias Diabéticas/patologia , Regulação para Baixo , Fator V/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Subunidades beta de Inibinas/genética , MicroRNAs/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Fatores de Transcrição/genética , Regulação para Cima
11.
Neurocase ; 25(1-2): 17-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30968732

RESUMO

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an adult-onset autosomal dominant leukoencephalopathy resulting from mutations affecting the tyrosine kinase domain of the colony stimulating factor receptor 1 protein (encoded by CSF1R). The clinical phenotypes reported with CSF1R mutations are variable. We present a case of a patient with a pathogenic variant in the CSF1R gene with clinical and imaging features suggestive of Dementia with Lewy Bodies (DLB). This case expands the known clinical presentations associated with CSF1R mutations.


Assuntos
Doença por Corpos de Lewy , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade
12.
Immunity ; 50(4): 796-811, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995500

RESUMO

The ß common chain cytokines GM-CSF, IL-3, and IL-5 regulate varied inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. Therapeutic interventions manipulating these cytokines are approved for use in some cancers as well as allergic and autoimmune disease, and others show promising early clinical activity. These approaches are based on our understanding of the inflammatory roles of these cytokines; however, GM-CSF also participates in the resolution of inflammation, and IL-3 and IL-5 may also have such properties. Here, we review the functions of the ß common cytokines in health and disease. We discuss preclinical and clinical data, highlighting the potential inherent in targeting these cytokine pathways, the limitations, and the important gaps in understanding of the basic biology of this cytokine family.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Inflamação/imunologia , Interleucina-3/imunologia , Interleucina-5/imunologia , Animais , Doenças Autoimunes/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/deficiência , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Hematopoese/imunologia , Humanos , Inflamação/terapia , Interleucina-3/antagonistas & inibidores , Interleucina-3/deficiência , Interleucina-3/genética , Interleucina-5/antagonistas & inibidores , Interleucina-5/deficiência , Interleucina-5/genética , Camundongos , Camundongos Knockout , Família Multigênica , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Receptores de Interleucina-3/genética , Receptores de Interleucina-3/imunologia , Receptores de Interleucina-5/genética , Receptores de Interleucina-5/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais , Relação Estrutura-Atividade , Vacinação , Cicatrização/imunologia
13.
Int J Mol Sci ; 20(6)2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917570

RESUMO

Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could be found in clinical familial and sporadic AD. To further elucidate the missing heritability in early-onset Alzheimer's disease (EOAD), we genetically characterized a Thai EOAD cohort by Next-Generation Sequencing (NGS) with a high depth of coverage, capturing variants in 50 previously recognized AD and other related disorders' genes. A novel mutation, APP p.V604M, and the known causative variant, PSEN1 p.E184G, were found in two of the familiar cases. Remarkably, among 61 missense variants were additionally discovered from 21 genes out of 50 genes, six potential mutations including MAPT P513A, LRRK2 p.R1628P, TREM2 p.L211P, and CSF1R (p.P54Q and pL536V) may be considered to be probably/possibly pathogenic and risk factors for other dementia leading to neuronal degeneration. All allele frequencies of the identified missense mutations were compared to 622 control individuals. Our study provides initial evidence that AD and other neurodegenerative diseases may represent shades of the same disease spectrum, and consideration should be given to offer exactly embracing genetic testing to patients diagnosed with EOAD. Our results need to be further confirmed with a larger cohort from this area.


Assuntos
Doença de Alzheimer/genética , Adulto , Idade de Início , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Presenilina-1/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores Imunológicos/genética , Proteínas tau/genética
14.
Mol Genet Genomic Med ; 7(4): e00595, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30729751

RESUMO

BACKGROUND: Colony-stimulating factor 1 receptor is a tyrosine kinase transmembrane protein that mediates proliferation, differentiation, and survival of monocytes/macrophages and microglia. CSF1R gene mutations cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an autosomal-dominantly inherited microgliopathy, leading to early onset dementia with high lethality. METHODS: By interdisciplinary assessment of a complex neuropsychiatric condition in a 44-year old female patient, we narrowed down the genetic diagnostic to CSF1R gene sequencing. Flow cytometric analyses of uncultivated peripheral blood monocytes were conducted sequentially to measure the cell surface CSF1 receptor and autophosphorylation levels. Monocyte subpopulations were monitored during disease progression. RESULTS: We identified a novel heterozygous deletion-insertion mutation c.2527_2530delinsGGCA, p.(Ile843_Leu844delinsGlyIle) in our patient with initial signs of HDLS. Marginally elevated cell surface CSF1 receptor levels with increased Tyr723 autophosphorylation suggest an enhanced receptor activity. Furthermore, we observed a shift in monocyte subpopulations during disease course. CONCLUSION: Our data indicate a mutation-related CSF1R gain-of-function, accompanied by an altered composition of the peripheral innate immune cells in our patient with HDLS. Since pharmacological targeting of CSF1R with tyrosine kinase inhibitors prevents disease progression in mouse models of neurodegenerative disorders, a potential pharmacological benefit of CSF1R inhibition remains to be elucidated for patients with HDLS.


Assuntos
Mutação com Ganho de Função , Leucoencefalopatias/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Feminino , Heterozigoto , Humanos , Leucoencefalopatias/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo
15.
PLoS Biol ; 17(2): e3000134, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30735499

RESUMO

Microglia are resident immune cells that play critical roles in maintaining the normal physiology of the central nervous system (CNS). Remarkably, microglia have an intrinsic capacity to repopulate themselves after acute ablation. However, the underlying mechanisms that drive such restoration remain elusive. Here, we characterized microglial repopulation both spatially and temporally following removal via treatment with the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. We show that microglia were replenished via self-renewal, with no contribution from nonmicroglial lineages, including Nestin+ progenitors and the circulating myeloid population. Interestingly, spatial analyses with dual-color labeling revealed that newborn microglia recolonized the parenchyma by forming distinctive clusters that maintained stable territorial boundaries over time, indicating the proximal expansive nature of adult microgliogenesis and the stability of microglia tiling. Temporal transcriptome profiling at different repopulation stages revealed that adult newborn microglia gradually regain steady-state maturity from an immature state that is reminiscent of the neonatal stage and follow a series of maturation programs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, interferon immune activation, and apoptosis. Importantly, we show that the restoration of microglial homeostatic density requires NF-κB signaling as well as apoptotic egress of excessive cells. In summary, our study reports key events that take place from microgliogenesis to homeostasis reestablishment.


Assuntos
Envelhecimento/genética , Encéfalo/metabolismo , Homeostase/genética , Microglia/metabolismo , NF-kappa B/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Envelhecimento/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Apoptose/genética , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Interferons/genética , Interferons/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Nestina/genética , Nestina/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Compostos Orgânicos/toxicidade , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Regeneração/genética , Transdução de Sinais , Transcriptoma
16.
J Immunol ; 202(4): 1186-1199, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30626692

RESUMO

The phosphatidylserine receptor TIM4, encoded by TIMD4, mediates the phagocytic uptake of apoptotic cells. We applied anti-chicken TIM4 mAbs in combination with CSF1R reporter transgenes to dissect the function of TIM4 in the chick (Gallus gallus). During development in ovo, TIM4 was present on the large majority of macrophages, but expression became more heterogeneous posthatch. Blood monocytes expressed KUL01, class II MHC, and CSF1R-mApple uniformly. Around 50% of monocytes were positive for surface TIM4. They also expressed many other monocyte-specific transcripts at a higher level than TIM4- monocytes. In liver, highly phagocytic TIM4hi cells shared many transcripts with mammalian Kupffer cells and were associated with uptake of apoptotic cells. Although they expressed CSF1R mRNA, Kupffer cells did not express the CSF1R-mApple transgene, suggesting that additional CSF1R transcriptional regulatory elements are required by these cells. By contrast, CSF1R-mApple was detected in liver TIM4lo and TIM4- cells, which were not phagocytic and were more abundant than Kupffer cells. These cells expressed CSF1R alongside high levels of FLT3, MHCII, XCR1, and other markers associated with conventional dendritic cells in mice. In bursa, TIM4 was present on the cell surface of two populations. Like Kupffer cells, bursal TIM4hi phagocytes coexpressed many receptors involved in apoptotic cell recognition. TIM4lo cells appear to be a subpopulation of bursal B cells. In overview, TIM4 is associated with phagocytes that eliminate apoptotic cells in the chick. In the liver, TIM4 and CSF1R reporters distinguished Kupffer cells from an abundant population of dendritic cell-like cells.


Assuntos
Fagócitos/imunologia , Receptores de Superfície Celular/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Animais , Anticorpos Monoclonais/imunologia , Galinhas , Receptores de Superfície Celular/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética
18.
Inflamm Bowel Dis ; 25(3): 547-560, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30124884

RESUMO

BACKGROUND: Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS: Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS: We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001). CONCLUSIONS: Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.


Assuntos
Doença de Crohn/patologia , Subunidade beta Comum dos Receptores de Citocinas/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Mutação de Sentido Incorreto , Neutrófilos/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Transcriptoma , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença de Crohn/genética , Doença de Crohn/metabolismo , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Lactente , Masculino , Neutrófilos/metabolismo , Prognóstico , Adulto Jovem
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(6): 828-831, 2018 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-30512156

RESUMO

OBJECTIVE: To identify differentially expressed genes in peripheral blood mononuclear cells between patients with continuous mild-to-moderate asthma and healthy controls using mRNA microarray in order to explore the underlying signaling pathways and clarify the roles of CD4+ T cells in the pathogenesis of asthma. METHODS: Global transcriptomic profiles of the CD4+ T cells were defined by using Agilent Sure Print G3 Human GE 8×60K microarray. Enrichment pathways were analyzed with Ingenuity Pathway Analysis (IPA) software. RESULTS: Compared with controls, 805 genes were up-regulated, 192 were down-regulated in asthma patients. Among these, the expression of 38 annotated genes have varied by 4 times or more. Expression of CD300A was inversely proportional to the absolute value of eosinophils (r=-0.89, P=0.02) as well as the proportion of eosinophils (rs=-0.94, P=0.004), while CSF1R was inversely proportional to PD20 (rs=-0.83, P=0.04) and AQLQ (r=-0.88, P=0.02) by correlation analysis. CONCLUSION: Numerous pathophysiological pathways may be involved in the pathogenesis of asthma. Above findings have provided a basis for the delineation the pathogenesis of asthma.


Assuntos
Asma/imunologia , Linfócitos T CD4-Positivos/citologia , Transcriptoma , Antígenos CD/genética , Estudos de Casos e Controles , Eosinófilos , Perfilação da Expressão Gênica , Humanos , Leucócitos Mononucleares , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores Imunológicos/genética
20.
Nat Commun ; 9(1): 5279, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30538245

RESUMO

Regulatory mechanisms controlling the pool size of spleen dendritic cells (DC) remain incompletely understood. DCs are continuously replenished from hematopoietic stem cells, and FLT3-mediated signals cell-intrinsically regulate homeostatic expansion of spleen DCs. Here we show that combining FLT3 and CSF1R-deficiencies results in specific and complete abrogation of spleen DCs in vivo. Spatiotemporally controlled CSF1R depletion reveals a cell-extrinsic and non-hematopoietic mechanism for DC pool size regulation. Lack of CSF1R-mediated signals impedes the differentiation of spleen macrophages of embryonic origin, and the resulted macrophage depletion during development or in adult mice results in loss of DCs. Moreover, embryo-derived macrophages are important for the physiologic regeneration of DC after activation-induced depletion in situ. In summary, we show that the differentiation of DC and their regeneration relies on ontogenetically distinct spleen macrophages, thereby providing a novel regulatory principle that may also be important for the differentiation of other hematopoietic cell types.


Assuntos
Células Dendríticas/citologia , Macrófagos/citologia , Camundongos/embriologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Animais , Diferenciação Celular , Células Dendríticas/metabolismo , Feminino , Macrófagos/metabolismo , Masculino , Camundongos/metabolismo , Camundongos Knockout , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Baço/citologia , Baço/metabolismo , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA