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1.
J Neurosci ; 44(19)2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38531632

RESUMO

BMAL2 (ARNTL2) is a paralog of BMAL1 that can form heterodimers with the other circadian factors CLOCK and NPAS2 to activate transcription of clock and clock-controlled genes. To assess a possible role of Bmal2 in the circadian regulation of metabolism, we investigated daily variations of energy metabolism, feeding behavior, and locomotor behavior, as well as ability to anticipate restricted food access in male mice knock-out for Bmal2 (B2KO). While their amount of food intake and locomotor activity were normal compared with wild-type mice, B2KO mice displayed increased adiposity (1.5-fold higher) and fasted hyperinsulinemia (fourfold higher) and tended to have lower energy expenditure at night. Impairment of the master clock in the suprachiasmatic nuclei was evidenced by the shorter free-running period (-14 min/cycle) of B2KO mice compared with wild-type controls and by a loss of daily rhythmicity in expression of intracellular metabolic regulators (e.g., Lipoprotein lipase and Uncoupling protein 2). The circadian window of eating was longer in B2KO mice. The circadian patterns of food intake and meal numbers were bimodal in control mice but not in B2KO mice. In response to restricted feeding, food-anticipatory activity was almost prevented in B2KO mice, suggesting altered food clock that controls anticipation of food availability. In the mediobasal hypothalamus of B2KO mice, expression of genes coding orexigenic neuropeptides (including Neuropeptide y and Agouti-Related Peptide) was downregulated, while Lipoprotein lipase expression lost its rhythmicity. Together, these data highlight that BMAL2 has major impacts on brain regulation of metabolic rhythms, sleep-wake cycle, and food anticipation.


Assuntos
Fatores de Transcrição ARNTL , Ritmo Circadiano , Metabolismo Energético , Comportamento Alimentar , Hipotálamo , Camundongos Knockout , Animais , Camundongos , Metabolismo Energético/fisiologia , Metabolismo Energético/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Masculino , Comportamento Alimentar/fisiologia , Ritmo Circadiano/fisiologia , Ritmo Circadiano/genética , Hipotálamo/metabolismo , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Atividade Motora/genética , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia
2.
Front Immunol ; 8: 287, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28424681

RESUMO

Abrogation of ICOS/ICOS ligand (ICOSL) costimulation prevents the onset of diabetes in the non-obese diabetic (NOD) mouse but, remarkably, yields to the development of a spontaneous autoimmune neuromyopathy. At the pathological level, ICOSL-/- NOD mice show stronger protection from insulitis than their ICOS-/- counterparts. Also, the ICOSL-/- NOD model carries a limited C57BL/6 region containing the Icosl nul mutation, but, in contrast to ICOS-/- NOD mice, no gene variant previously reported as associated to NOD diabetes. Therefore, we aimed at providing a detailed characterization of the ICOSL-/- NOD model. The phenotype observed in ICOSL-/- NOD mice is globally similar to that observed in ICOS-/- and ICOS-/-ICOSL-/- double-knockout NOD mice, manifested by a progressive locomotor disability first affecting the front paws as observed by catwalk analysis and a decrease in grip test performance. The pathology remains limited to peripheral nerve and striated muscle. The muscle disease is characterized by myofiber necrosis/regeneration and an inflammatory infiltrate composed of CD4+ T-cells, CD8+ T-cells, and myeloid cells, resembling human myositis. Autoimmune neuromyopathy can be transferred to NOD.scid recipients by CD4+ but not by CD8+ T-cells isolated from 40-week-old female ICOSL-/- NOD mice. The predominant role of CD4+ T-cells is further demonstrated by the observation that neuromyopathy does not develop in CIITA-/-ICOSL-/- NOD in contrast to ß2microglobulin-/-ICOSL-/- NOD mice. Also, the cytokine profile of CD4+ T-cells infiltrating muscle and nerve of ICOSL-/- NOD mice is biased toward a Th1 pattern. Finally, adoptive transfer experiments show that diabetes development requires expression of ICOSL, in contrast to neuromyopathy. Altogether, the deviation of autoimmunity from the pancreas to skeletal muscles in the absence of ICOS/ICOSL signaling in NOD mice is strictly dependent on CD4+ T-cells, leads to myofiber necrosis and regeneration. It provides the first mouse model of spontaneous autoimmune myopathy akin to human myositis.

3.
Diabetes ; 63(6): 2148-57, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24520124

RESUMO

The circadian rhythm-related aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2) gene has been identified as a candidate gene for the murine type 1 diabetes locus Idd6.3. Previous studies suggested a role in expansion of CD4(+)CD25(-) T cells, and this then creates an imbalance in the ratio between T-effector and CD4(+)CD25(+) T-regulator cells. Our transcriptome analyses identify the interleukin 21 (IL21) gene (Il21) as a direct target of ARNTL2. ARNTL2 binds in an allele-specific manner to the RNA polymerase binding site of the Il21 promoter and inhibits its expression in NOD.C3H congenic mice carrying C3H alleles at Idd6.3. IL21 is known to promote T-cell expansion, and in agreement with these findings, mice with C3H alleles at Idd6.3 produce lower numbers of CD4(+)IL21(+) and CD4(+) and CD8(+) T cells compared with mice with NOD alleles at Idd6.3. Our results describe a novel and rather unexpected role for Arntl2 in the immune system that lies outside of its predicted function in circadian rhythm regulation.


Assuntos
Fatores de Transcrição ARNTL/genética , Ritmo Circadiano/genética , Diabetes Mellitus Tipo 1/genética , Interleucinas/metabolismo , Fatores de Transcrição ARNTL/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Imunoprecipitação da Cromatina , Diabetes Mellitus Tipo 1/metabolismo , Regulação para Baixo , Citometria de Fluxo , Predisposição Genética para Doença , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos NOD , RNA Interferente Pequeno/genética
4.
Immunogenetics ; 62(9): 585-92, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20676886

RESUMO

The genetic locus Idd6 is involved in type 1 diabetes development in the non-obese diabetic (NOD) mouse through its effect on the immune system and in particular, on T cell activities. Analysis of congenic strains for Idd6 has established the Aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2) as a likely candidate gene. In this study we investigate the role of Arntl2 in the autoimmune disease and T cell activation. An Arntl2 expressing plasmid was transfected into CD4(+) T cells by nucleofection. Expression levels of cytokines and CD4(+) T cell activation markers, cell death, apoptosis, and cell proliferation rates were characterized in ex vivo experiments whilst in vivo the transfected cells were transferred into NOD.SCID mice to monitor diabetes development. The results demonstrate that Arntl2 overexpression leads to inhibition of CD4(+) T cell proliferation and decreases in their diabetogenic activity without influence on the expression levels of cytokines, CD4(+) T cell activation markers, cell death, and apoptosis. Our findings suggest that Arntl2 at the Idd6 locus may act via the inhibition of CD4(+) T cell proliferation and the reduction in the diabetogenic activity of CD4(+) T cells to protect against autoimmune type 1 diabetes in the NOD mice.


Assuntos
Fatores de Transcrição ARNTL/genética , Linfócitos T CD4-Positivos/imunologia , Ritmo Circadiano , Diabetes Mellitus Tipo 1/prevenção & controle , Ativação Linfocitária , Baço/imunologia , Regulação para Cima/fisiologia , Animais , Apoptose , Western Blotting , Proliferação de Células , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Plasmídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/metabolismo , Transfecção
5.
Leuk Res ; 34(3): 289-93, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19540588

RESUMO

The Aiolos transcription factor plays a crucial role in the control of lymphocyte differentiation and proliferation. The expression of Aiolos isoform has been studied in lymphoid pathologies but nothing is known about its expression in unaffected human hematopoietic subpopulations. In this manuscript we show for the first time the differential Aiolos expression at the RNA and protein level in hematopoietic cell subpopulations. B cells express higher levels of Aiolos than NK and T cells while monocytes express almost undetectable levels of Aiolos. Moreover, human CD34 (+) progenitors do not express Aiolos. We did not observe significant difference when comparing naive to memory T and B cells, but we observed an important difference between Bright and Dim NK cells. Furthermore, we show that, in addition to hematopoietic cells, non hematopoietic cell lines such as MCF-7, SW480, HEK, PC3 and HeLa also express Aiolos.


Assuntos
Linfócitos B/metabolismo , Fator de Transcrição Ikaros/biossíntese , Células Matadoras Naturais/metabolismo , Monócitos/metabolismo , Linfócitos T/metabolismo , Western Blotting , Linhagem Celular , Separação Celular , Sangue Fetal/citologia , Sangue Fetal/metabolismo , Citometria de Fluxo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Subpopulações de Linfócitos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
J Immunol ; 181(3): 1753-9, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18641312

RESUMO

The number and function of immunoregulatory invariant NKT (iNKT) cells are genetically controlled. A defect of iNKT cell ontogeny and function has been implicated as one causal factor of NOD mouse susceptibility to type 1 diabetes. Other factors of diabetes susceptibility, such as a decrease of regulatory T cell function or an increase in TLR1 expression, are corrected in diabetes-resistant Idd6 NOD.C3H 6.VIII congenic mice. Thus, we surmised that the iNKT cell defects found in NOD mice may also be rescued in congenic mice. Unexpectedly, we found, in both the thymus and the periphery, a 50% reduction in iNKT cell number in NOD.C3H 6.VIII mice as compared with NOD mice. This reduction only affected CD4(+) iNKT cells, and left the double negative iNKT cells unchanged. In parallel, the production of IL-4 and IFN-gamma following alpha-GalCer stimulation was proportionally reduced. Using three subcongenic strains, we have narrowed down the region controlling iNKT development within Idd6 (5.8 Mb) to Idd6.2 region (2.5 Mb). Idd6 region had no effect on NK cell number and in vivo cytotoxic activity. These results indicate that the role of iNKT cells in diabetes development is equivocal and more complex than initially considered. In addition, they bring strong evidence that the regulation of CD4(+) iNKT cell production is independent from that of DN iNKT cells, and involves genes of the Idd6 locus.


Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Cromossomos de Mamíferos/genética , Cromossomos de Mamíferos/imunologia , Homeostase/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Citotoxicidade Imunológica/imunologia , Interferon gama/biossíntese , Interleucina-4/biossíntese , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Camundongos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Timo/imunologia
7.
Autoimmunity ; 36(4): 241-6, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14563018

RESUMO

Three type 1 diabetes associated regions on distal mouse chromosome 6 have recently been defined by the construction and analysis of a series of congenic strains, carrying C3H/HeJ genomic material on a NOD/Lt genetic background. Whilst NOD/Lt alleles at the most distal locus Idd6 confer susceptibility, C3H/HeJ alleles confer resistance to diabetes. Idd6 overlaps with a locus controlling low rates of proliferation in immature NOD-thymocytes, suggesting that Idd6 could be controlling diabetes development through an effect on T cell proliferation rates. Candidates for Idd6 therefore include genes, which are implicated in the immune system and/or in the control of cell proliferation rates, such as Lrmp (Jaw1), Bcat1 and Kras2 that map to the Idd6 candidate region. In the present study, we have undertaken an expression and mutational analysis of all three genes. A surprisingly large number of polymorphisms and amino acid changes were identified in both Lrmp and Bcat1 indicating that they are candidates for Idd6. The two genes are located within a genomic interval of about 3 Mb that contains a large number of single nucleotide polymorphisms (SNP) and which has possibly been derived from distinct ancestral haplotypes in the C3H/HeJ and NOD/Lt strains.


Assuntos
Diabetes Mellitus Tipo 1/genética , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas/genética , Proteínas/imunologia , Transaminases , Animais , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Polimorfismo de Nucleotídeo Único , RNA/química , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
8.
Nat Rev Immunol ; 3(3): 243-52, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12658272

RESUMO

Autoimmune diseases are, in general, under complex genetic control and subject to strong interactions between genetics and the environment. Greater knowledge of the underlying genetics will provide immunologists with a framework for study of the immune dysregulation that occurs in such diseases. Ascertaining the number of genes that are involved and their characterization have, however, proven to be difficult. Improved methods of genetic analysis and the availability of a draft sequence of the complete mouse genome have markedly improved the outlook for such research, and they have emphasized the advantages of mice as a model system. In this review, we provide an overview of the genetic analysis of autoimmune diseases and of the crucial role of congenic and consomic mouse strains in such research.


Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Camundongos Congênicos/genética , Camundongos Congênicos/imunologia , Animais , Modelos Animais de Doenças , Variação Genética/imunologia , Humanos , Camundongos , Locos de Características Quantitativas/imunologia
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