Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.962
Filtrar
1.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445345

RESUMO

Chondrosarcoma is a malignant bone tumor that is characterized by high metastatic potential and marked resistance to radiation and chemotherapy. The knowledge that adipokines facilitate the initiation, progression, metastasis, and treatment resistance of various tumors has driven several in vitro and in vivo investigations into the effects of adipokines resistin, leptin, and adiponectin upon the development and progression of chondrosarcomas. Another adipokine, visfatin, is known to regulate tumor progression and metastasis, although how this molecule may affect chondrosarcoma metastasis is unclear. Here, we found that visfatin facilitated cellular migration via matrix metalloproteinase-2 (MMP-2) production in human chondrosarcoma cells and overexpression of visfatin enhanced lung metastasis in a mouse model of chondrosarcoma. Visfatin-induced stimulation of MMP-2 synthesis and activation of the AP-1 transcription factor facilitated chondrosarcoma cell migration via the ERK, p38, and JNK signaling pathways. This evidence suggests that visfatin is worth targeting in the treatment of metastatic chondrosarcoma.


Assuntos
Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Citocinas/fisiologia , Metaloproteinase 2 da Matriz/genética , Nicotinamida Fosforribosiltransferase/fisiologia , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Condrossarcoma/genética , Condrossarcoma/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição AP-1/fisiologia , Células Tumorais Cultivadas
2.
Front Immunol ; 12: 613461, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456900

RESUMO

Allergy is an IgE-dependent type-I hypersensitivity reaction that can lead to life-threatening systemic symptoms such as anaphylaxis. In the pathogenesis of the allergic response, the common upstream event is the binding of allergens to specific IgE, inducing cross-linking of the high-affinity FcεRI on mast cells, triggering cellular degranulation and the release of histamine, proteases, lipids mediators, cytokines and chemokines with inflammatory activity. A number of novel therapeutic options to curb mast cell activation are in the pipeline for the treatment of severe allergies. In addition to anti-IgE therapy and allergen-specific immunotherapy, monoclonal antibodies targeted against several key Th2/alarmin cytokines (i.e. IL-4Rα, IL-33, TSLP), active modification of allergen-specific IgE (i.e. inhibitory compounds, monoclonal antibodies, de-sialylation), engagement of inhibitory receptors on mast cells and allergen-specific adjuvant vaccines, are new promising options to inhibit the uncontrolled release of mast cell mediators upon allergen exposure. In this review, we critically discuss the novel approaches targeting mast cells limiting allergic responses and the immunological mechanisms involved, with special interest on food allergy treatment.


Assuntos
Hipersensibilidade Alimentar/terapia , Imunoglobulina E/imunologia , Mastócitos/fisiologia , Anticorpos Anti-Idiotípicos/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/fisiologia , Dessensibilização Imunológica , Hipersensibilidade Alimentar/imunologia , Humanos , Mastócitos/efeitos dos fármacos
3.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360874

RESUMO

Osteoarthritis (OA) is still a recalcitrant musculoskeletal disease on account of its complex biochemistry and mechanical stimulations. Apart from stimulation by external mechanical forces, the regulation of intracellular mechanics in chondrocytes has also been linked to OA development. Recently, visfatin has received significant attention because of the clinical finding of the positive correlation between its serum/synovial level and OA progression. However, the precise mechanism involved is still unclear. This study determined the effect of visfatin on intracellular mechanics and catabolism in human primary chondrocytes isolated from patients. The intracellular stiffness of chondrocytes was analyzed by the particle-tracking microrheology method. It was shown that visfatin damages the microtubule and microfilament networks to influence intracellular mechanics to decrease the intracellular elasticity and viscosity via glycogen synthase kinase 3ß (GSK3ß) inactivation induced by p38 signaling. Further, microtubule network destruction in human primary chondrocytes is predominantly responsible for the catabolic effect of visfatin on the cyclooxygenase 2 upregulation. The present study shows a more comprehensive interpretation of OA development induced by visfatin through biochemical and biophysical perspectives. Finally, the role of GSK3ß inactivation, and subsequent regulation of intracellular mechanics, might be considered as theranostic targets for future drug development for OA.


Assuntos
Condrócitos , Citocinas/fisiologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Nicotinamida Fosforribosiltransferase/fisiologia , Osteoartrite , Citoesqueleto de Actina/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Humanos , Microtúbulos/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Cultura Primária de Células
4.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281281

RESUMO

Atopic dermatitis (AD) is a prototypic inflammatory disease that presents with intense itching. The pathophysiology of AD is multifactorial, involving environmental factors, genetic susceptibility, skin barrier function, and immune responses. A recent understanding of pruritus transmission provides more information about the role of pruritogens in the pathogenesis of AD. There is evidence that pruritogens are not only responsible for eliciting pruritus, but also interact with immune cells and act as inflammatory mediators, which exacerbate the severity of AD. In this review, we discuss the interaction between pruritogens and inflammatory molecules and summarize the targeted therapies for AD.


Assuntos
Dermatite Atópica/etiologia , Prurido/etiologia , Colestase/complicações , Colestase/fisiopatologia , Colestase/terapia , Citocinas/fisiologia , Dermatite Atópica/fisiopatologia , Dermatite Atópica/terapia , Histamina/fisiologia , Humanos , Mediadores da Inflamação/fisiologia , Modelos Biológicos , Neuroimunomodulação/fisiologia , Prurido/fisiopatologia , Prurido/terapia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia
5.
Anticancer Res ; 41(6): 2781-2793, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083268

RESUMO

BACKGROUND/AIM: This study explored the mechanisms of the allogeneic graft versus leukemia effect in acute lymphoblastic leukemia (ALL) cells by examining whether they change gene expression in the post-transplant environment containing cytokines and the immunosuppressant cyclosporine, and if such changes affect ALL cell survival. MATERIALS AND METHODS: RNASeq was used to assess leukemia global gene expression and flow cytometry to measure ALL survival in the presence of T cells, NK cells, cytokines, and cyclosporine. RESULTS: A total of 4,805 genes were differentially expressed. Gene set enrichment analysis demonstrated up-regulation of biological processes related to cytokine responses, control of viral infection, and regulation of leukocyte function including proliferation. Down-regulated genes were related to mesenchymal tissue morphogenesis. ALL cells exposed to cytokines and cyclosporine retained susceptibility to T and NK cell killing, and also exhibited increased cell death without exposure to killer cells. CONCLUSION: A significant portion of the graft versus leukemia effect may be mediated by cytokines and cyclosporine.


Assuntos
Sobrevivência Celular/genética , Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Criança , Ciclosporina/farmacologia , Citocinas/sangue , Citocinas/fisiologia , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transplante Homólogo
6.
Front Immunol ; 12: 676088, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122438

RESUMO

As a highly inflammatory form of programmed cell death, pyroptosis is triggered by pro-inflammatory signals and associated with inflammation. It is characterized by cell swelling and large bubbles emerging from the plasma membrane, which release cytokines during inflammation. Compared with other types of cell death, pyroptosis has a distinct morphology and mechanism and involves special inflammasome cascade pathways. However, the inflammasome mechanism through which endometrial epithelial cell pyroptosis occurs in LPS-mediated inflammation remains unclear. We confirmed that there was an increased mRNA and protein expression of the IL-6, TNF-α, IL-1ß, IL-18 cytokines, the inflammasome molecules NLRP3, CASPASE-1, CASPASE-4, and GSDMD in LPS-induced primary bovine endometrial epithelial cells (BEECs) in an in vitro established inflammatory model using ELISA, real-time PCR (RT-PCR), vector construction and transfection, and Western blotting. Scanning electron microscopy and lactate dehydrogenase (LDH) activity assays revealed induced cell membrane rupture, which is the main characteristic of pyroptosis. In conclusion, the cytolytic substrate GSDMD's cleavage by caspase-1 or caspase-4 through the NLRP3 classical and non-classical inflammasome pathways, GSDMD N-terminus bind to the plasma membrane to form pores and release IL -18, IL-1ß cause cell death during LPS induced BEECs inflammation.


Assuntos
Endométrio/efeitos dos fármacos , Inflamassomos/fisiologia , Lipopolissacarídeos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Piroptose/efeitos dos fármacos , Animais , Bovinos , Células Cultivadas , Citocinas/fisiologia , Endométrio/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Inflamação/etiologia , Transdução de Sinais/fisiologia
7.
Front Immunol ; 12: 627360, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981299

RESUMO

Angioedema with eosinophilia is classified into two types: episodic angioedema with eosinophilia (EAE), known as Gleich's syndrome, and non-episodic angioedema with eosinophilia (NEAE). We present the case of a young lactating woman with non-episodic angioedema. She had no history of parasitic or nonparasitic infections. Physical examination showed striking, non-pitting edema in both lower extremities. Her weight had not changed significantly throughout the course of the illness. She exhibited no other symptoms, and her vital signs were normal. There was no evidence of anemia, hypoalbuminemia, thyroid dysfunction, heart failure, renal failure, or postpartum cardiomyopathy. Based on these findings, we diagnosed her with angioedema with eosinophilia. Given the scarcity of information about this condition, we explored the dynamics between cytokines/chemokines and edema in this patient. We successfully quantified the edema by bioimpedance analysis. In addition, we revealed the involvement of interleukin-5 (IL-5), thymus- and activation-regulated chemokine/C-C motif chemokine ligand-17 (TARC/CCL-17), eotaxin-3/CCL-26, tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), monocyte chemotactic protein-4/CCL-13 (MCP-4/CCL-13), eotaxin-1/CCL-11, and regulated on activation, normal T expressed and secreted/CCL-5 (RANTES/CCL-5) in NEAE. Lastly, we elucidated the strong association between these parameters. To the best of our knowledge, this is the first such study of its kind.


Assuntos
Angioedema/imunologia , Eosinofilia/imunologia , Adulto , Quimiocinas/análise , Quimiocinas/fisiologia , Citocinas/análise , Citocinas/fisiologia , Impedância Elétrica , Feminino , Humanos , Lactação
8.
Mol Neurobiol ; 58(9): 4477-4486, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34033061

RESUMO

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of human COVID-19, not only causes flu-like symptoms and gut microbiome complications but a large number of infected individuals also experience a host of neurological symptoms including loss of smell and taste, seizures, difficulty concentrating, decreased alertness, and brain inflammation. Although SARS-CoV-2 infections are not more prevalent in Parkinson's disease patients, a higher mortality rate has been reported not only associated with older age and longer disease duration, but also through several mechanisms, such as interactions with the brain dopaminergic system and through systemic inflammatory responses. Indeed, a number of the neurological symptoms seen in COVID-19 patients, as well as the alterations in the gut microbiome, are also prevalent in patients with Parkinson's disease. Furthermore, biochemical pathways such as oxidative stress, inflammation, and protein aggregation have shared commonalities between Parkinson's disease and COVID-19 disease progression. In this review, we describe and compare the numerous similarities and intersections between neurodegeneration in Parkinson's disease and RNA viral infections, emphasizing the current SARS-CoV-2 global health crisis.


Assuntos
COVID-19/fisiopatologia , Microbioma Gastrointestinal , Doença de Parkinson/fisiopatologia , SARS-CoV-2 , Idoso , COVID-19/complicações , COVID-19/mortalidade , Transtornos Cognitivos/etiologia , Citocinas/fisiologia , Dieta , Progressão da Doença , Disbiose/etiologia , Disbiose/fisiopatologia , Humanos , Inflamação , Metais Pesados/toxicidade , Modelos Neurológicos , Degeneração Neural , Bulbo Olfatório/fisiopatologia , Bulbo Olfatório/virologia , Estresse Oxidativo , Doença de Parkinson/etiologia , Guias de Prática Clínica como Assunto , Agregação Patológica de Proteínas/etiologia , Infecções por Vírus de RNA/metabolismo , Infecções por Vírus de RNA/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Transtornos das Sensações/etiologia , alfa-Sinucleína/metabolismo
9.
Mol Neurobiol ; 58(9): 4487-4494, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34036488

RESUMO

Headache is the most common neurological symptom in COVID-19, reported in 6.5 to 34% of patients. Few studies have analyzed its characteristics, and some of them included cases without laboratory confirmation or reported only critical patients. We aimed to analyze the clinical characteristics of COVID-19 associated headache in laboratory-confirmed cases. We conducted a retrospective evaluation of patients with COVID-19 and neurological symptoms. Patients who reported headache answered an interview about its clinical characteristics. Twenty-four patients with COVID-19 associated headache completed the interview. Mean age of patients was 53.8 (standard deviation-17.44), and 14 out of 24 (58.3%) were male. The majority (75%) had no previous history of headache. Fever was documented in 19 out of the 24 patients (79.1%). Headache was predominantly bifrontal or holocranial, in pressure, during hours, worsening with cough or physical activity. COVID-19 headache tends to appear in the first days of symptoms, be either frontal or holocranial and last for days. The quality of pain in pressure and the worsening with cough or physical activity were reported in most cases. We have not found any characteristic that could differentiate COVID-19 associated headache from other causes of headache, possibly because of its multifactorial mechanism.


Assuntos
COVID-19/complicações , Cefaleia/etiologia , SARS-CoV-2 , Adolescente , Adulto , Anti-Hipertensivos/uso terapêutico , COVID-19/diagnóstico , COVID-19/epidemiologia , Teste para COVID-19 , Comorbidade , Citocinas/fisiologia , Endotélio Vascular/fisiopatologia , Endotélio Vascular/virologia , Feminino , Febre/etiologia , Cefaleia/fisiopatologia , Humanos , Inflamação , Masculino , Modelos Biológicos , Neoplasias/epidemiologia , Estudos Retrospectivos , Avaliação de Sintomas , Nervo Trigêmeo/virologia , Adulto Jovem
10.
Biochem Biophys Res Commun ; 555: 168-174, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33819747

RESUMO

When animals are infected with helminthic parasites, resistant hosts mount type II helper T (Th2) immune responses to expel worms. Recent studies have clearly shown that epithelial cell-derived cytokines contribute to the induction of Th2 immune responses. Here we demonstrate the role of endogenous thymic stromal lymphopoietin (TSLP) for protection against Strongyloides venezuelensis (S. venezuelensis) infection, utilizing TSLP receptor-deficient Crlf2-/- mice. The number of eggs per gram of feces (EPG) and worm burden were significantly higher in Crlf2-/- mice than in wild type (WT) mice. S. venezuelensis infection induced Tslp mRNA expression in the skin, lung, and intestine and also facilitated the accumulation of mast cells in the intestine in a TSLP-dependent manner. Furthermore, CD4+ T cells from S. venezuelensis-infected Crlf2-/- mice showed diminished capacity to produce Th2 cytokines in the early stage of infection. Finally, CD4+ cell-depleted Crlf2-/- mice still showed higher EPG counts and worm burden than CD4+ cell-depleted WT mice, indicating that TSLP contributes to protecting mice against S. venezuelensis infection in both CD4+ T cell-dependent and -independent manners.


Assuntos
Linfócitos T CD4-Positivos/parasitologia , Citocinas/fisiologia , Estrongiloidíase/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Resistência à Doença/fisiologia , Fezes/parasitologia , Interações Hospedeiro-Parasita , Imunoglobulina E/sangue , Imunoglobulinas/genética , Intestinos/parasitologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores de Citocinas/genética , Estrongiloidíase/parasitologia
11.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808333

RESUMO

Thymic stromal lymphopoietin (TSLP) contributes to asthmatic disease. The concentrations of protective IgA may be reduced in the respiratory tract of asthma patients. We investigated how homeostatic short TSLP (shTSLP) and asthma-associated long TSLP (loTSLP) regulate IgA production. B cells from healthy donors were stimulated in the presence or absence of shTSLP or loTSLP; the concentrations of IgA, IgM, IgE, and IgG antibodies were determined in cell culture supernatants; and B cells were analyzed by flow cytometry. LoTSLP, but not shTSLP, suppressed the secretion of IgA but not of IgE. The type 2 cytokine IL-4, which in addition to loTSLP contributes to asthmatic disease, did not affect the production of IgA or the frequency of IgA+ B cells. Instead, IL-4 increased IgG production, especially of the subclasses IgG2 and IgG4. LoTSLP inhibited IgA secretion by sorted memory B cells but not by naïve B cells. Although loTSLP inhibited IgA production, the vitamin A metabolite retinoic acid promoted the secretion of IgA, also in the presence of loTSLP, suggesting that vitamin A may promote IgA production in asthma. Our data demonstrate that asthma-associated loTSLP negatively regulates the secretion of IgA, which may negatively impact the surveillance of mucosal surfaces in asthma.


Assuntos
Asma/imunologia , Citocinas/imunologia , Imunoglobulina A/metabolismo , Asma/complicações , Asma/metabolismo , Linfócitos B/metabolismo , Células Cultivadas , Citocinas/metabolismo , Citocinas/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Imunoglobulina A/imunologia , Masculino
12.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800867

RESUMO

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson's disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.


Assuntos
Envelhecimento/imunologia , Células Apresentadoras de Antígenos/imunologia , Subpopulações de Linfócitos B/imunologia , Mitocôndrias/fisiologia , Regeneração/imunologia , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Citocinas/fisiologia , DNA/metabolismo , DNA Mitocondrial/metabolismo , Reposicionamento de Medicamentos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Homeostase , Humanos , Imunidade Inata , Inflamação , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Metformina/farmacologia , Metformina/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Imunologia de Transplantes , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/fisiopatologia
13.
Nat Metab ; 3(4): 513-522, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33846641

RESUMO

Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colchicina/farmacologia , Citocinas/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Células Mieloides/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Antioxidantes/farmacologia , Colchicina/farmacocinética , Simulação por Computador , Citocinas/biossíntese , Fator 15 de Diferenciação de Crescimento/genética , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Peritonite/induzido quimicamente , Peritonite/prevenção & controle , Proteína Tirosina Fosfatase não Receptora Tipo 6/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
14.
Cell Host Microbe ; 29(6): 959-974.e7, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-33894128

RESUMO

Microbiota play critical roles in regulating colitis and colorectal cancer (CRC). However, it is unclear how the microbiota generate protective immunity against these disease states. Here, we find that loss of the innate and adaptive immune signaling molecule, TAK1, in myeloid cells (Tak1ΔM/ΔM) yields complete resistance to chemical-induced colitis and CRC through microbiome alterations that drive protective immunity. Tak1ΔM/ΔM mice exhibit altered microbiota that are critical for resistance, with antibiotic-mediated disruption ablating protection and Tak1ΔM/ΔM microbiota transfer conferring protection against colitis or CRC. The altered microbiota of Tak1ΔM/ΔM mice promote IL-1ß and IL-6 signaling pathways, which are required for induction of protective intestinal Th17 cells and resistance. Specifically, Odoribacter splanchnicus is abundant in Tak1ΔM/ΔM mice and sufficient to induce intestinal Th17 cell development and confer resistance against colitis and CRC in wild-type mice. These findings identify specific microbiota strains and immune mechanisms that protect against colitis and CRC.


Assuntos
Bacteroidetes/metabolismo , Colite/microbiologia , Neoplasias Colorretais/microbiologia , Citocinas/fisiologia , Microbioma Gastrointestinal , MAP Quinase Quinase Quinases/fisiologia , Células Th17/metabolismo , Animais , Colite/induzido quimicamente , Colite/metabolismo , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Interações entre Hospedeiro e Microrganismos , Imunidade Inata , Interleucina-1beta/fisiologia , Interleucina-6/fisiologia , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/metabolismo , Transdução de Sinais , Células Th17/imunologia
15.
FASEB J ; 35(5): e21450, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33788980

RESUMO

Agouti-related protein (AgRP) neurons in the arcuate nucleus of the hypothalamus regulates food intake and whole-body metabolism. NAD+ regulates multiple cellular processes controlling energy metabolism. Yet, its role in hypothalamic AgRP neurons to control food intake is poorly understood. Here, we aimed to assess whether genetic deletion of nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme in NAD+ production, affects AgRP neuronal function to impact whole-body metabolism and food intake. Metabolic parameters during fed and fasted states, and upon systemic ghrelin and leptin administration were studied in AgRP-specific Nampt knockout (ARNKO) mice. We monitored neuropeptide expression levels and density of AgRP neurons in ARNKO mice from embryonic to adult age. NPY cells were used to determine effects of NAMPT inhibition on neuronal viability, energy status, and oxidative stress in vitro. In these cells, NAD+ depletion reduced ATP levels, increased oxidative stress, and promoted cell death. Agrp expression in the hypothalamus of ARNKO mice gradually decreased after weaning due to progressive AgRP neuron degeneration. Adult ARNKO mice had normal glucose and insulin tolerance, but exhibited an elevated respiratory exchange ratio (RER) when fasted. Remarkably, fasting-induced food intake was unaffected in ARNKO mice when evaluated in metabolic cages, but fasting- and ghrelin-induced feeding and body weight gain decreased in ARNKO mice when evaluated outside metabolic cages. Collectively, deletion of Nampt in AgRP neurons causes progressive neurodegeneration and impairs fasting and ghrelin responses in a context-dependent manner. Our data highlight an essential role of Nampt in AgRP neuron function and viability.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Citocinas/fisiologia , Ingestão de Alimentos , Jejum , Grelina/farmacologia , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Nicotinamida Fosforribosiltransferase/fisiologia , Proteína Relacionada com Agouti/genética , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo
16.
Yakugaku Zasshi ; 141(3): 359-368, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33642504

RESUMO

Microglia are immune cells resident in the central nervous system (CNS). It has been gradually clarified that microglia play various roles at the developmental stage of the CNS. From embryonic to early postnatal age, microglia remove apoptotic cells by phagocytosis and refine the neural circuits by synaptic pruning. In addition, microglia promote the proliferation and differentiation of neural stem cells by releasing physiologically active substances. Our group has focused on the physiological actions of microglia via cytokines and chemokines at the early postnatal developmental stage. We found that a large number of activated microglia accumulate in the early postnatal subventricular zone (SVZ). We demonstrated that the these SVZ microglia facilitate neurogenesis and oligodendrogenesis via inflammatory cytokines including IL-1ß, TNFα, IL-6, IFNγ. We have also found that microglia regulate the functional maturation of the blood brain barrier (BBB) and identified the cytokines and chemokines involved in the effects of microglia. These findings indicate that microglia are physiologically more important than ever thought to reveal robust brain functions. Furthermore, the new mode of microglial action may lead to the discovery of drug targets of the incurable CNS diseases.


Assuntos
Sistema Nervoso Central/embriologia , Sistema Nervoso Central/crescimento & desenvolvimento , Quimiocinas/metabolismo , Citocinas/metabolismo , Microglia/imunologia , Microglia/fisiologia , Animais , Apoptose/imunologia , Barreira Hematoencefálica/embriologia , Barreira Hematoencefálica/crescimento & desenvolvimento , Diferenciação Celular , Proliferação de Células , Quimiocinas/fisiologia , Citocinas/fisiologia , Humanos , Mediadores da Inflamação/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese , Plasticidade Neuronal/fisiologia , Fagocitose
17.
Nat Rev Immunol ; 21(8): 526-541, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33649606

RESUMO

Interactions between the immune system and the nervous system have been described mostly in the context of diseases. More recent studies have begun to reveal how certain immune cell-derived soluble effectors, the cytokines, can influence host behaviour even in the absence of infection. In this Review, we contemplate how the immune system shapes nervous system function and how it controls the manifestation of host behaviour. Interactions between these two highly complex systems are discussed here also in the context of evolution, as both may have evolved to maximize an organism's ability to respond to environmental threats in order to survive. We describe how the immune system relays information to the nervous system and how cytokine signalling occurs in neurons. We also speculate on how the brain may be hardwired to receive and process information from the immune system. Finally, we propose a unified theory depicting a co-evolution of the immune system and host behaviour in response to the evolutionary pressure of pathogens.


Assuntos
Citocinas/imunologia , Citocinas/fisiologia , Sistema Imunitário/imunologia , Sistema Imunitário/fisiologia , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologia , Animais , Comportamento Animal/fisiologia , Evolução Biológica , Encéfalo/imunologia , Encéfalo/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Comportamento de Doença/fisiologia , Infecções/imunologia , Infecções/fisiopatologia , Infecções/psicologia , Modelos Imunológicos , Modelos Neurológicos , Transdução de Sinais/imunologia , Transdução de Sinais/fisiologia
18.
Life Sci ; 275: 119356, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33737080

RESUMO

AIMS: Growth and differentiation factor 15 (GDF15) is a stress-related factor, which implicated in various diseases. This study aimed to investigate the role of GDF15 in LPS-mediated inflammation and to explore the potential underlying molecular mechanisms in human nasal epithelial cells (HNEpCs). MAIN METHODS: HNEpCs were treated with LPS. GDF15 loss-of-function and gain-of-function experiments were performed. The expression of GDF15 by quantitative real-time PCR (RT-qPCR). The mRNA levels and secretion of inflammatory cytokines and MUC5AC were assessed by RT-qPCR and ELISA kits. LY294002 (PI3K inhibitor) and 740Y-P (PI3K agonist) were utilized to interfere with PI3k/Akt pathway. The relationship between GDF15 and ATF4 was identified by chromatin immunoprecipitation (ChIP) and luciferase reporter assay. KEY FINDINGS: We observed that LPS triggered GDF15 expression. GDF15 ablation reduced the mRNA levels and secretion of inflammatory cytokines. GDF15 silencing led to the reduction of the MUC5AC mRNA level, protein level and secretion in response to LPS. Enhanced expression of GDF15 showed the opposite results. Furthermore, we found that GDF15 deficiency inhibited activation of the PI3K/Akt pathway, LY294002 treatment further enhanced the role of GDF15 suppression in inflammation and MUC5AC expression, while 740Y-P administration partly reversed the biological activities of GDF15 silencing. ATF4 could bind to the promoter of GDF15 and positively regulate GDF15 expression. Depression of ATF4 diminished the secretion of inflammatory cytokines and MUC5AC via regulation of GDF15. SIGNIFICANCE: Our data suggest that GDF15 is regulated by ATF4 and suppresses LPS-induced inflammation and MUC5AC in human nasal epithelial cells through the PI3K/Akt pathway.


Assuntos
Fator 4 Ativador da Transcrição/fisiologia , Fator 15 de Diferenciação de Crescimento/fisiologia , Inflamação/metabolismo , Mucina-5AC/metabolismo , Mucosa Nasal/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator 4 Ativador da Transcrição/metabolismo , Células Cultivadas , Imunoprecipitação da Cromatina , Citocinas/metabolismo , Citocinas/fisiologia , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Inflamação/fisiopatologia , Lipopolissacarídeos/farmacologia , Mucina-5AC/fisiologia , Mucosa Nasal/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real
19.
JCI Insight ; 6(3)2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33554957

RESUMO

Obesity and obesity-related diseases like type 2 diabetes (T2D) are prominent global health issues; therefore, there is a need to better understand the mechanisms underlying these conditions. The onset of obesity is characterized by accumulation of proinflammatory cells, including Ly6chi monocytes (which differentiate into proinflammatory macrophages) and neutrophils, in metabolic tissues. This shift toward chronic, low-grade inflammation is an obese-state hallmark and highly linked to metabolic disorders and other obesity comorbidities. The mechanisms that induce and maintain increased inflammatory myelopoiesis are of great interest, with a recent focus on how obesity affects more primitive hematopoietic cells. The hematopoietic system is constantly replenished by proper regulation of hematopoietic stem and progenitor (HSPC) pools in the BM. While early research suggests that chronic obesity promotes expansion of myeloid-skewed HSPCs, the involvement of the hematopoietic stem cell (HSC) niche in regulating obesity-induced myelopoiesis remains undefined. In this review, we explore the role of the multicellular HSC niche in hematopoiesis and inflammation, and the potential contribution of this niche to the hematopoietic response to obesity. This review further aims to summarize the potential HSC niche involvement as a target of obesity-induced inflammation and a driver of obesity-induced myelopoiesis.


Assuntos
Células-Tronco Hematopoéticas/patologia , Inflamação/etiologia , Obesidade/complicações , Animais , Citocinas/fisiologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Hematopoese , Células-Tronco Hematopoéticas/fisiologia , Humanos , Inflamação/patologia , Inflamação/fisiopatologia , Mediadores da Inflamação/fisiologia , Camundongos , Modelos Biológicos , Mielopoese , Obesidade/patologia , Obesidade/fisiopatologia , Osteoblastos/patologia , Osteoblastos/fisiologia , Nicho de Células-Tronco/fisiologia , Sistema Nervoso Simpático/fisiopatologia
20.
Basic Res Cardiol ; 116(1): 12, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33629195

RESUMO

The benefits of remote ischaemic conditioning (RIC) have been difficult to translate to humans, when considering traditional outcome measures, such as mortality and heart failure. This paper reviews the recent literature of the anti-inflammatory effects of RIC, with a particular focus on the innate immune response and cytokine inhibition. Given the current COVID-19 pandemic, the inflammatory hypothesis of cardiac protection is an attractive target on which to re-purpose such novel therapies. A PubMed/MEDLINE™ search was performed on July 13th 2020, for the key terms RIC, cytokines, the innate immune system and inflammation. Data suggest that RIC attenuates inflammation in animals by immune conditioning, cytokine inhibition, cell survival and the release of anti-inflammatory exosomes. It is proposed that RIC inhibits cytokine release via a reduction in nuclear factor kappa beta (NF-κB)-mediated NLRP3 inflammasome production. In vivo, RIC attenuates pro-inflammatory cytokine release in myocardial/cerebral infarction and LPS models of endotoxaemia. In the latter group, cytokine inhibition is associated with a profound survival benefit. Further clinical trials should establish whether the benefits of RIC in inflammation can be observed in humans. Moreover, we must consider whether uncomplicated MI and elective surgery are the most suitable clinical conditions in which to test this hypothesis.


Assuntos
Citocinas/fisiologia , Imunidade Inata , Inflamação/terapia , Precondicionamento Isquêmico Miocárdico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , COVID-19/complicações , Sobrevivência Celular , Vesículas Extracelulares/fisiologia , Humanos , Imunidade Humoral , Inflamação/sangue , Traumatismo por Reperfusão Miocárdica/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...