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1.
Proc Natl Acad Sci U S A ; 116(38): 19090-19097, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31481626

RESUMO

Aberrant T cell development is a pivotal risk factor for autoimmune disease; however, the underlying molecular mechanism of T cell overactivation is poorly understood. Here, we identified NF-κB-inducing kinase (NIK) and IkB kinase α (IKKα) in thymic epithelial cells (TECs) as essential regulators of T cell development. Mouse TEC-specific ablation of either NIK or IKKα resulted in severe T cell-mediated inflammation, injury, and fibrosis in the liver and lung, leading to premature death within 18 d of age. NIK or IKKα deficiency abrogated medullary TEC development, and led to breakdown of central tolerance, production of autoreactive T cells, and fatal autoimmune destruction in the liver and lung. TEC-specific ablation of NIK or IKKα also impaired thymic T cell development from the double-negative through the double-positive stages and inhibited peripheral B cell development. These results unravel a hitherto unrecognized essential role of TEC-intrinsic NIK and IKKα pathways in autoimmunity and T cell-instigated chronic liver and lung diseases.

2.
Mol Cell ; 75(3): 644-660.e5, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398325

RESUMO

Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.

3.
Nat Immunol ; 20(6): 677-686, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110312

RESUMO

Consumption of a high-energy Western diet triggers mild adaptive ß cell proliferation to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. In the present study we show that the toll-like receptors TLR2 and TLR4 inhibited the diet-induced replication of ß cells in mice and humans. The combined, but not the individual, loss of TLR2 and TLR4 increased the replication of ß cells, but not that of α cells, leading to enlarged ß cell area and hyperinsulinemia in diet-induced obesity. Loss of TLR2 and TLR4 increased the nuclear abundance of the cell cycle regulators cyclin D2 and Cdk4 in a manner dependent on the signaling mediator Erk. These data reveal a regulatory mechanism controlling the proliferation of ß cells in diet-induced obesity and suggest that selective targeting of the TLR2/TLR4 pathways may reverse ß cell failure in patients with diabetes.


Assuntos
Células Secretoras de Insulina/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Animais , Proliferação de Células , Ciclina D2/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Insulina/sangue , Insulina/metabolismo , Células Secretoras de Insulina/ultraestrutura , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Knockout , Complexos Multiproteicos/metabolismo , Obesidade/tratamento farmacológico , Parabiose , Ligação Proteica , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
4.
Proc Natl Acad Sci U S A ; 115(2): E263-E272, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29279393

RESUMO

Cell encapsulation has been shown to hold promise for effective, long-term treatment of type 1 diabetes (T1D). However, challenges remain for its clinical applications. For example, there is an unmet need for an encapsulation system that is capable of delivering sufficient cell mass while still allowing convenient retrieval or replacement. Here, we report a simple cell encapsulation design that is readily scalable and conveniently retrievable. The key to this design was to engineer a highly wettable, Ca2+-releasing nanoporous polymer thread that promoted uniform in situ cross-linking and strong adhesion of a thin layer of alginate hydrogel around the thread. The device provided immunoprotection of rat islets in immunocompetent C57BL/6 mice in a short-term (1-mo) study, similar to neat alginate fibers. However, the mechanical property of the device, critical for handling and retrieval, was much more robust than the neat alginate fibers due to the reinforcement of the central thread. It also had facile mass transfer due to the short diffusion distance. We demonstrated the therapeutic potential of the device through the correction of chemically induced diabetes in C57BL/6 mice using rat islets for 3 mo as well as in immunodeficient SCID-Beige mice using human islets for 4 mo. We further showed, as a proof of concept, the scalability and retrievability in dogs. After 1 mo of implantation in dogs, the device could be rapidly retrieved through a minimally invasive laparoscopic procedure. This encapsulation device may contribute to a cellular therapy for T1D because of its retrievability and scale-up potential.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/fisiologia , Alginatos , Animais , Diabetes Mellitus Experimental/terapia , Dimetilformamida , Cães , Ácido Glucurônico , Ácidos Hexurônicos , Humanos , Hidrogéis , Camundongos , Camundongos SCID , Polimetil Metacrilato , Ratos
5.
Cell Rep ; 16(10): 2630-2640, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27568564

RESUMO

Endoplasmic reticulum (ER)-associated degradation (ERAD) is a principal mechanism that targets ER-associated proteins for cytosolic proteasomal degradation. Here, our data demonstrate a critical role for the Sel1L-Hrd1 complex, the most conserved branch of ERAD, in early B cell development. Loss of Sel1L-Hrd1 ERAD in B cell precursors leads to a severe developmental block at the transition from large to small pre-B cells. Mechanistically, we show that Sel1L-Hrd1 ERAD selectively recognizes and targets the pre-B cell receptor (pre-BCR) for proteasomal degradation in a BiP-dependent manner. The pre-BCR complex accumulates both intracellularly and at the cell surface in Sel1L-deficient pre-B cells, leading to persistent pre-BCR signaling and pre-B cell proliferation. This study thus implicates ERAD mediated by Sel1L-Hrd1 as a key regulator of B cell development and reveals the molecular mechanism underpinning the transient nature of pre-BCR signaling.


Assuntos
Linfócitos B/citologia , Linfócitos B/metabolismo , Pontos de Checagem do Ciclo Celular , Degradação Associada com o Retículo Endoplasmático , Proteínas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Antígenos CD19/metabolismo , Ciclo Celular , Tamanho Celular , Camundongos Endogâmicos C57BL , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Receptores de Antígenos de Linfócitos B , Especificidade por Substrato , Fator de Transcrição CHOP/metabolismo
6.
Mol Biol Cell ; 27(3): 483-90, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26631554

RESUMO

Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases quality of life. Endoplasmic reticulum (ER)-associated degradation (ERAD) is responsible for the clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn's disease (CD). Consistent with this observation, laboratory mice with enterocyte-specific Sel1L deficiency (Sel1L(ΔIEC)) develop spontaneous enteritis and have increased susceptibility to Toxoplasma gondii-induced ileitis. This is associated with profound defects in Paneth cells and a disproportionate increase of Ruminococcus gnavus, a mucolytic bacterium with known association with CD. Surprisingly, whereas both ER stress sensor IRE1α and effector CHOP are activated in the small intestine of Sel1L(ΔIEC) mice, they are not solely responsible for ERAD deficiency-associated lesions seen in the small intestine. Thus our study points to a constitutive role of Sel1L-Hrd1 ERAD in epithelial cell biology and the pathogenesis of intestinal inflammation in CD.


Assuntos
Enterócitos/metabolismo , Proteínas/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose , Duodeno/metabolismo , Duodeno/patologia , Estresse do Retículo Endoplasmático , Degradação Associada com o Retículo Endoplasmático , Endorribonucleases/fisiologia , Enterite/metabolismo , Enterite/patologia , Feminino , Microbioma Gastrointestinal , Haploinsuficiência , Homeostase , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Celulas de Paneth/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Fator de Transcrição CHOP/fisiologia
7.
Nat Cell Biol ; 17(12): 1546-55, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26551274

RESUMO

Endoplasmic reticulum (ER)-associated degradation (ERAD) represents a principle quality control mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unexplored. Here we discover that IRE1α, the sensor of the unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. ERAD-mediated IRE1α degradation occurs under basal conditions in a BiP-dependent manner, requires both the intramembrane hydrophilic residues of IRE1α and the lectin protein OS9, and is attenuated by ER stress. ERAD deficiency causes IRE1α protein stabilization, accumulation and mild activation both in vitro and in vivo. Although enterocyte-specific Sel1L-knockout mice (Sel1L(ΔIEC)) are viable and seem normal, they are highly susceptible to experimental colitis and inflammation-associated dysbiosis, in an IRE1α-dependent but CHOP-independent manner. Hence, Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1α signalling in vivo by managing its protein turnover.


Assuntos
Degradação Associada com o Retículo Endoplasmático/genética , Endorribonucleases/genética , Proteínas Serina-Treonina Quinases/genética , Resposta a Proteínas não Dobradas/genética , Animais , Sequência de Bases , Western Blotting , Células Cultivadas , Retículo Endoplasmático/metabolismo , Endorribonucleases/metabolismo , Enterócitos/metabolismo , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Lectinas/genética , Lectinas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/genética , Proteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
8.
Sci Rep ; 5: 14124, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26369936

RESUMO

CD1d-dependent NKT cells have been extensively studied; however, the function of CD8(+)NKT-like cells, which are CD1d-independent T cells with NK markers, remains unknown. Here, we report that CD1d-independent CD8(+)NKT-like cells, which express both T cell markers (TCRß and CD3) and NK cell receptors (NK1.1, CD49b and NKG2D), are activated and significantly expanded in mice immunized with GFP-expressing dendritic cells. Distinct from CD1d-dependent NKT cells, CD8(+)NKT-like cells possess a diverse repertoire of TCRs and secrete high levels of IFN-gamma but not IL-4. CD8(+)NKT-like cell development is normal in CD1d(-/-) mice, which suggests that CD8(+)NKT-like cells undergo a unique development pathway that differs from iNKT cells. Further functional analyses show that CD8(+)NKT-like cells suppress T-cell responses through elimination of dendritic cells in an antigen-specific manner. Adoptive transfer of antigen-specific CD8(+)NKT-like cells into RIP-OVA mice prevented subsequent development of diabetes in the animals induced by activated OT-I CD8 T cells. Our study suggests that CD8(+)NKT-like cells can function as antigen-specific suppressive cells to regulate the immune response through killing antigen-bearing DCs. Antigen-specific down regulation may provide an active and precise method for constraining an excessive immune response and avoiding bypass suppression of necessary immune responses to other antigens.


Assuntos
Antígenos de Superfície/imunologia , Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica , Células Dendríticas/imunologia , Imunomodulação , Células T Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/metabolismo , Imunização , Imunofenotipagem , Contagem de Linfócitos , Camundongos , Células T Matadoras Naturais/metabolismo , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/metabolismo
9.
Biomaterials ; 37: 40-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25453936

RESUMO

Cell encapsulation holds enormous potential to treat a number of hormone deficient diseases and endocrine disorders. We report a simple and universal approach to fabricate robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) with macroscopic dimensions. In this design, we take advantage of the well-known capillary action that holds wetting liquid in porous media. By impregnating the highly porous electrospun nanofiber membranes of pre-made tubular or planar devices with hydrogel precursor solutions and subsequent crosslinking, we obtained various nanofiber-enabled hydrogel devices. This approach is broadly applicable and does not alter the water content or the intrinsic chemistry of the hydrogels. The devices retained the properties of both the hydrogel (e.g. the biocompatibility) and the nanofibers (e.g. the mechanical robustness). The facile mass transfer was confirmed by encapsulation and culture of different types of cells. Additional compartmentalization of the devices enabled paracrine cell co-cultures in single implantable devices. Lastly, we provided a proof-of-concept study on potential therapeutic applications of the devices by encapsulating and delivering rat pancreatic islets into chemically-induced diabetic mice. The diabetes was corrected for the duration of the experiment (8 weeks) before the implants were retrieved. The retrieved devices showed minimal fibrosis and as expected, live and functional islets were observed within the devices. This study suggests that the design concept of NEEDs may potentially help to overcome some of the challenges in the cell encapsulation field and therefore contribute to the development of cell therapies in future.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/instrumentação , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Nanofibras/química , Animais , Linhagem Celular Tumoral , Humanos , Transplante das Ilhotas Pancreáticas , Masculino , Fenômenos Mecânicos , Camundongos Endogâmicos C57BL , Nanofibras/ultraestrutura , Ratos Sprague-Dawley
10.
Cell Rep ; 8(1): 137-49, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-24953658

RESUMO

Chronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome, but how it induces mortality remains unclear. Here, we show that chronic intake of a high-fat diet (HFD), not a low-fat diet, leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors 2 and 4 (DKO). Diet-induced pulmonary lesions are blocked by antibiotic treatment and are transmissible to wild-type mice upon either cohousing or fecal transplantation, pointing to the existence of bacterial pathogens. Indeed, diet and innate deficiency exert significant impact on gut microbiota composition. Thus, chronic intake of HFD promotes severe pulmonary damage and mortality in DKO mice in part via gut dysbiosis, a finding that may be important for immunodeficient patients, particularly those on chemotherapy or radiotherapy, where gut-microbiota-caused conditions are often life threatening.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Disbiose/complicações , Pneumopatias/etiologia , Microbiota , Receptor 2 Toll-Like/deficiência , Receptor 4 Toll-Like/deficiência , Animais , Disbiose/etiologia , Disbiose/imunologia , Imunidade Inata , Intestinos/imunologia , Intestinos/microbiologia , Pneumopatias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética
11.
Proc Natl Acad Sci U S A ; 111(5): E582-91, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24453213

RESUMO

Suppressor/Enhancer of Lin-12-like (Sel1L) is an adaptor protein for the E3 ligase hydroxymethylglutaryl reductase degradation protein 1 (Hrd1) involved in endoplasmic reticulum-associated degradation (ERAD). Sel1L's physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we show that Sel1L is indispensable for Hrd1 stability, ER homeostasis, and survival. Acute loss of Sel1L leads to premature death in adult mice within 3 wk with profound pancreatic atrophy. Contrary to current belief, our data show that mammalian Sel1L is required for Hrd1 stability and ERAD function both in vitro and in vivo. Sel1L deficiency disturbs ER homeostasis, activates ER stress, attenuates translation, and promotes cell death. Serendipitously, using a biochemical approach coupled with mass spectrometry, we found that Sel1L deficiency causes the aggregation of both small and large ribosomal subunits. Thus, Sel1L is an indispensable component of the mammalian Hrd1 ERAD complex and ER homeostasis, which is essential for protein translation, pancreatic function, and cellular and organismal survival.


Assuntos
Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Homeostase , Mamíferos/metabolismo , Proteínas/metabolismo , Animais , Atrofia , Técnicas de Cultura de Células , Morte Celular , Proliferação de Células , Sobrevivência Celular , Retículo Endoplasmático/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Pâncreas Exócrino/anormalidades , Pâncreas Exócrino/metabolismo , Pâncreas Exócrino/patologia , Pâncreas Exócrino/ultraestrutura , Polirribossomos/metabolismo , Biossíntese de Proteínas , Estabilidade Proteica , Vesículas Secretórias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Resposta a Proteínas não Dobradas
12.
PLoS One ; 8(11): e78841, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24250814

RESUMO

The transcriptional co-regulator host cell factor-1 (HCF-1) plays critical roles in promoting cell cycle progression in diverse cell types, and in maintaining self-renewal of embryonic stem cells, but its role in pancreatic ß-cell function has not been investigated. Immunhistochemistry of mouse pancreas revealed nuclear expression of HCF-1 in pancreatic islets. Reducing HCF-1 expression in the INS-1 pancreatic ß-cell line resulted in reduced cell proliferation, reduced glucose-stimulated insulin secretion, and reduced expression of the critical ß-cell transcription factor Pdx1. HCF-1 is a known co-activator of the E2F1 transcription factor, and loss of E2F1 results in pancreatic ß-cell dysfunction and reduced expression of Pdx1. Therefore we wondered whether HCF-1 might be required for E2F1 regulation of Pdx1. Chromatin immunoprecipitation experiments revealed that HCF-1 and E2F1 co-localize to the Pdx1 promoter. These results indicate that HCF-1 represents a novel transcriptional regulator required for maintaining pancreatic ß-cell function.


Assuntos
Fator C1 de Célula Hospedeira/genética , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Animais , Linhagem Celular , Proliferação de Células/genética , Cromatina/genética , Cromatina/metabolismo , Fator de Transcrição E2F1/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Proteínas de Homeodomínio/genética , Fator C1 de Célula Hospedeira/metabolismo , Camundongos , Regiões Promotoras Genéticas , Ratos , Transativadores/genética
13.
J Clin Invest ; 123(1): 261-71, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23257358

RESUMO

Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13-/-) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13-/- mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.


Assuntos
Glucose/metabolismo , Interleucina-13/metabolismo , Fígado/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Gluconeogênese/genética , Gluconeogênese/imunologia , Glucose/genética , Glucose/imunologia , Hiperglicemia/genética , Hiperglicemia/imunologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Resistência à Insulina/genética , Resistência à Insulina/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/imunologia , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Fígado/imunologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
14.
Dev Cell ; 23(6): 1141-52, 2012 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-23237951

RESUMO

Here we identify and characterize a cytoskeletal myosin protein required for IRE1α oligomerization, activation, and signaling. Proteomic screening identified nonmuscle myosin heavy chain IIB (NMHCIIB), a subunit of nonmuscle myosin IIB (NMIIB), as an ER stress-dependent interacting protein specific to IRE1α. Loss of NMIIB compromises XBP1s and UPR target gene expression with no effect on the PERK pathway. Mechanistically, NMIIB is required for IRE1α aggregation and foci formation under ER stress. The NMIIB-mediated effect on IRE1α signaling is in part dependent on the phosphorylation of myosin regulatory light chain and the actomyosin contractility of NMIIB. Biologically, the function of NMIIB in ER stress response is conserved as both mammalian cells and C. elegans lacking NMIIB exhibit hypersensitivity to ER stress. Thus, optimal IRE1α activation and signaling require concerted coordination between the ER and cytoskeleton.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Miosina não Muscular Tipo IIB/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Animais , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Linhagem Celular , Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático/genética , Camundongos , Cadeias Pesadas de Miosina/genética , Miosina não Muscular Tipo IIB/genética , Fosforilação , Interferência de RNA , RNA Interferente Pequeno , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição/metabolismo , Proteína 1 de Ligação a X-Box , eIF-2 Quinase/metabolismo
15.
J Biol Chem ; 287(29): 24378-86, 2012 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-22645141

RESUMO

Inflammation in adipose tissue plays an important role in the pathogenesis of obesity-associated complications. However, the detailed cellular events underlying the inflammatory changes at the onset of obesity have not been characterized. Here we show that an acute HFD challenge is unexpectedly associated with elevated alternative (M2) macrophage polarization in adipose tissue mediated by Natural Killer T (NKT) cells. Upon 4d HFD feeding, NKT cells are activated, promote M2 macrophage polarization and induce arginase 1 expression via interleukin (IL)-4 in adipose tissue, not in the liver. In NKT-deficient CD1d(-/-) mice, M2 macrophage polarization in adipose tissue is reduced while systemic glucose homeostasis and insulin tolerance are impaired upon 4d HFD challenge. Thus, our study demonstrate, for the first time to our knowledge, that acute HFD feeding is associated with remarkably pronounced and dynamic immune responses in adipose tissue, and adipose-resident NKT cells may link acute HFD feeding with inflammation.


Assuntos
Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Interleucina-4/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Células T Matadoras Naturais/citologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Western Blotting , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interleucina-4/genética , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/citologia , Células Estromais/efeitos dos fármacos
16.
J Biol Chem ; 287(17): 13561-71, 2012 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-22396530

RESUMO

Natural killer T (NKT) cells are important therapeutic targets in various disease models and are under clinical trials for cancer patients. However, their function in obesity and type 2 diabetes remains unclear. Our data show that adipose tissues of both mice and humans contain a population of type 1 NKT cells, whose abundance decreases with increased adiposity and insulin resistance. Although loss-of-function of NKT cells had no effect on glucose tolerance in animals with prolonged high fat diet feeding, activation of NKT cells by lipid agonist α-galactosylceramide enhances alternative macrophage polarization in adipose tissue and improves glucose homeostasis in animals at different stages of obesity. Furthermore, the effect of NKT cells is largely mediated by the IL-4/STAT6 signaling axis in obese adipose tissue. Thus, our data identify a novel therapeutic target for the treatment of obesity-associated inflammation and type 2 diabetes.


Assuntos
Tecido Adiposo/citologia , Glucose/metabolismo , Células Matadoras Naturais/metabolismo , Macrófagos/citologia , Tecido Adiposo/metabolismo , Adulto , Animais , Índice de Massa Corporal , Feminino , Teste de Tolerância a Glucose , Glicolipídeos/metabolismo , Homeostase , Humanos , Inflamação/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Obesidade/metabolismo
17.
Annu Rev Nutr ; 32: 261-86, 2012 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-22404118

RESUMO

The fields of immunology and metabolism are rapidly converging on adipose tissue. During obesity, many immune cells infiltrate or populate in adipose tissue and promote a low-grade chronic inflammation. Studies to date have suggested that perturbation of inflammation is critically linked to nutrient metabolic pathways and to obesity-associated complications such as insulin resistance and type 2 diabetes. Despite these advances, however, many open questions remain including how inflammatory responses are initiated and maintained, how nutrients impact the function of various immune populations, and how inflammatory responses affect systemic insulin sensitivity. Here we review recent studies on the roles of various immune cells at different phases of obesity and discuss molecular mechanisms underlying obesity-associated inflammation. Better understanding of the events occurring in adipose tissue will provide insights into the pathophysiological role of inflammation in obesity and shed light on the pathogenesis of obesity-associated metabolic syndrome.


Assuntos
Tecido Adiposo/imunologia , Obesidade/imunologia , Imunidade Adaptativa , Tecido Adiposo/metabolismo , Animais , Humanos , Imunidade Inata , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Obesidade/sangue , Obesidade/metabolismo
18.
Diabetes ; 61(6): 1471-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22415881

RESUMO

Inflammasome activation in adipose tissue has been implicated in obesity-associated insulin resistance and type 2 diabetes. However, when and how inflammasome is activated in adipose tissue remains speculative. Here we test the hypothesis that extracellular ATP, a potent stimulus of inflammasome in macrophages via purinergic receptor P2X, ligand-gated ion channel, 7 (P2X(7)), may play a role in inflammasome activation in adipose tissue in obesity. Our data show that inflammasome is activated in adipose tissue upon 8-week feeding of 60% high-fat diet (HFD), coinciding with the onset of hyperglycemia and hyperinsulinemia as well as the induction of P2X(7) in adipose tissue. Unexpectedly, P2X(7)-deficient animals on HFD exhibit no changes in metabolic phenotypes, inflammatory responses, or inflammasome activation when compared with the wild-type controls. Similar observations have been obtained in hematopoietic cell-specific P2X(7)-deficient animals generated by bone marrow transplantation. Thus, we conclude that inflammasome activation in adipose tissue in obesity coincides with the onset of hyperglycemia and hyperinsulinemia but, unexpectedly, is not mediated by the ATP-P2X(7) signaling axis. The nature of the inflammasome-activating danger signal(s) in adipose tissue in obesity remains to be characterized.


Assuntos
Trifosfato de Adenosina/metabolismo , Tecido Adiposo/metabolismo , Inflamassomos/metabolismo , Obesidade/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais/fisiologia , Trifosfato de Adenosina/genética , Animais , Dieta Hiperlipídica , Gorduras na Dieta/metabolismo , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Inflamação/genética , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Receptores Purinérgicos P2X7/genética
19.
J Biol Chem ; 286(26): 23591-9, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21592961

RESUMO

Activation of immune cells, including macrophages and CD8(+) T cells, contributes significantly to the advancement of obesity and its associated medical complications, such as atherosclerosis, insulin resistance, and type 2 diabetes. However, how the activation of these immune cells is regulated in vivo remains largely unexplored. Here we show that a group of immature myeloid cells with cell surface markers of Gr-1(+) CD11b(+) are highly enriched in peripheral tissues (i.e. liver and adipose tissues) during obesity. Down-regulation of these cells in obese animals significantly increases inflammation and impairs insulin sensitivity and glucose tolerance, whereas elevation of these cells via adoptive transfer has the opposite effects. Mechanistically, we show that under obese conditions, the Gr-1(+) cells suppress proliferation and induce apoptosis of CD8(+) T cells and are capable of skewing differentiation of macrophages into insulin-sensitizing, alternatively activated M2 macrophages. Taken together, our study demonstrates that immature myeloid cells provide a checks-and-balances platform to counter proinflammatory immune cells in the liver and adipose tissue during obesity to prevent overt immune responses.


Assuntos
Antígeno CD11b , Resistência à Insulina/imunologia , Células Mieloides/imunologia , Obesidade/imunologia , Receptores de Superfície Celular , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/imunologia , Proliferação de Células , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Inflamação/imunologia , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Obesos , Células Mieloides/patologia , Obesidade/patologia
20.
PLoS One ; 4(11): e7869, 2009 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-19924241

RESUMO

The central nervous system (CNS) is generally regarded as a site of immune privilege, whether the antigen presenting cells (APCs) are involved in the immune homeostasis of the CNS is largely unknown. Microglia and DCs are major APCs in physiological and pathological conditions, respectively. In this work, primary microglia and microglia-like cells obtained by co-culturing mature dendritic cells with CNS endothelial cells in vitro were functional evaluated. We found that microglia not only cannot prime CD4 T cells but also inhibit mature DCs (maDCs) initiated CD4 T cells proliferation. More importantly, endothelia from the CNS can differentiate maDCs into microglia-like cells (MLCs), which possess similar phenotype and immune inhibitory function as microglia. Soluble factors including NO lie behind the suppression of CD4 T cell proliferation induced by both microglia and MLCs. All the data indicate that under physiological conditions, microglia play important roles in maintaining immune homeostasis of the CNS, whereas in a pathological situation, the infiltrated DCs can be educated by the local microenvironment and differentiate into MLCs with inhibitory function.


Assuntos
Linfócitos T CD4-Positivos/citologia , Células Dendríticas/citologia , Microglia/metabolismo , Animais , Encéfalo/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Proliferação de Células , Separação Celular , Técnicas de Cocultura , Células Endoteliais/citologia , Citometria de Fluxo , Camundongos , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Fenótipo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Molécula 1 de Adesão de Célula Vascular/biossíntese
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