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1.
Immunity ; 52(6): 1039-1056.e9, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32392463

RESUMO

The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.


Assuntos
Plasticidade Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunidade , Macrófagos/imunologia , Macrófagos/metabolismo , Infecções por Respirovirus/etiologia , Apresentação de Antígeno , Biomarcadores , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Imunofenotipagem , Interferon Tipo I/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Especificidade de Órgãos/imunologia , Receptores Fc/metabolismo , Infecções por Respirovirus/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fatores de Transcrição , Viroses/genética , Viroses/imunologia , Viroses/metabolismo , Viroses/virologia
2.
EMBO Rep ; 23(12): e55233, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36194667

RESUMO

The anti-inflammatory protein A20 serves as a critical brake on NF-κB signaling and NF-κB-dependent inflammation. In humans, polymorphisms in or near the TNFAIP3/A20 gene have been associated with several inflammatory disorders, including rheumatoid arthritis (RA), and experimental studies in mice have demonstrated that myeloid-specific A20 deficiency causes the development of a severe polyarthritis resembling human RA. Myeloid A20 deficiency also promotes osteoclastogenesis in mice, suggesting a role for A20 in the regulation of osteoclast differentiation and bone formation. We show here that osteoclast-specific A20 knockout mice develop severe osteoporosis, but not inflammatory arthritis. In vitro, osteoclast precursor cells from A20 deficient mice are hyper-responsive to RANKL-induced osteoclastogenesis. Mechanistically, we show that A20 is recruited to the RANK receptor complex within minutes of ligand binding, where it restrains NF-κB activation independently of its deubiquitinating activity but through its zinc finger (ZnF) 4 and 7 ubiquitin-binding functions. Together, these data demonstrate that A20 acts as a regulator of RANK-induced NF-κB signaling to control osteoclast differentiation, assuring proper bone development and turnover.


Assuntos
NF-kappa B , Humanos , Animais , Camundongos
3.
Mult Scler ; 24(3): 290-300, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28277099

RESUMO

BACKGROUND: Phagocytes, such as macrophages and microglia, are key effector cells in the pathophysiology of multiple sclerosis (MS). It is widely accepted that they instigate and promote neuroinflammatory and neurodegenerative events in MS. An increasing amount of studies indicate that Siglec-1, also known CD169, is a marker for activated phagocytes in inflammatory disorders. OBJECTIVE: In this study, we set out to define how CD169+ phagocytes contribute to neuroinflammation in MS. METHODS: CD169-diphtheria toxin receptor (DTR) mice, which express human DTR under control of the CD169 promoter, were used to define the impact of CD169+ cells on neuroinflammation. Flow cytometry and immunohistochemistry were utilized to determine the expression and distribution of CD169. RESULTS: We show that CD169 is highly expressed by lesional and circulating phagocytes in MS and experimental autoimmune encephalomyelitis (EAE). Our data further indicate that CD169 represents a selective marker for early activated microglia in MS and EAE lesions. Depletion of CD169+ cells markedly reduced neuroinflammation and ameliorated disease symptoms in EAE-affected mice. CONCLUSION: Our findings indicate that CD169+ cells promote neuroinflammation. Furthermore, they suggest that CD169+ phagocytes play a key role in the pathophysiology of MS. Hence, targeting CD169+ phagocytes may hold therapeutic value for MS.


Assuntos
Biomarcadores , Encefalomielite Autoimune Experimental/diagnóstico , Inflamação/diagnóstico , Esclerose Múltipla/diagnóstico , Fagócitos , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
4.
Cancer Immunol Immunother ; 65(11): 1365-1375, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27585789

RESUMO

Ly49E is a member of the Ly49 family of NK receptors and is distinct from other members of this family on the basis of its structural properties, expression pattern and ligand recognition. Importantly, Ly49E receptor expression is high on small intestinal and colonic intraepithelial lymphocytes (IELs). Intestinal IELs are regulators of the mucosal immune system and contribute to front-line defense at the mucosal barrier, including anti-tumor immune response. Whereas most Ly49 receptors have MHC class-I ligands, we showed that Ly49E is instead triggered by urokinase plasminogen activator (uPA). uPA has been extensively implicated in tumor development, where increased uPA expression correlates with poor prognosis. As such, we investigated the role of Ly49E receptor expression on intestinal IELs in the anti-tumor immune response. For this purpose, we compared Ly49E wild-type mice to Ly49E knockout mice in two established tumor models: ApcMin/+-mediated and azoxymethane-induced intestinal cancer. Our results indicate that Ly49E expression on IELs does not influence the development or progression of intestinal cancer.


Assuntos
Carcinoma in Situ/imunologia , Epitélio/imunologia , Neoplasias Intestinais/imunologia , Linfócitos/imunologia , Subfamília A de Receptores Semelhantes a Lectina de Células NK/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Azoximetano , Carcinogênese , Carcinoma in Situ/induzido quimicamente , Carcinoma in Situ/genética , Modelos Animais de Doenças , Epitélio/patologia , Regulação Neoplásica da Expressão Gênica , Imunidade Celular , Neoplasias Intestinais/induzido quimicamente , Neoplasias Intestinais/genética , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Subfamília A de Receptores Semelhantes a Lectina de Células NK/genética , Carga Tumoral , Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
5.
JCI Insight ; 9(10)2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38713534

RESUMO

The homeostasis of IgG is maintained by the neonatal Fc receptor, FcRn. Consequently, antagonism of FcRn to reduce endogenous IgG levels is an emerging strategy for treating antibody-mediated autoimmune disorders using either FcRn-specific antibodies or an engineered Fc fragment. For certain FcRn-specific antibodies, this approach has resulted in reductions in the levels of serum albumin, the other major ligand transported by FcRn. Cellular and molecular analyses of a panel of FcRn antagonists have been carried out to elucidate the mechanisms leading to their differential effects on albumin homeostasis. These analyses have identified 2 processes underlying decreases in albumin levels during FcRn blockade: increased degradation of FcRn and competition between antagonist and albumin for FcRn binding. These findings have potential implications for the design of drugs to modulate FcRn function.


Assuntos
Antígenos de Histocompatibilidade Classe I , Receptores Fc , Receptores Fc/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunoglobulina G/metabolismo , Animais , Transporte Proteico/efeitos dos fármacos , Albumina Sérica/metabolismo , Camundongos , Ligação Proteica
6.
Front Immunol ; 13: 892534, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757719

RESUMO

Serum albumin (SA), the most abundant soluble protein in the body, maintains plasma oncotic pressure and regulates the distribution of vascular fluid and has a range of other important functions. The goals of this review are to expand clinical knowledge regarding the functions of SA, elucidate effects of dysregulated SA concentration, and discuss the clinical relevance of hypoalbuminemia resulting from various diseases. We discuss potential repercussions of SA dysregulation on cholesterol levels, liver function, and other processes that rely on its homeostasis, as decreased SA concentration has been shown to be associated with increased risk for cardiovascular disease, hyperlipidemia, and mortality. We describe the anti-inflammatory and antioxidant properties of SA, as well as its ability to bind and transport a plethora of endogenous and exogenous molecules. SA is the primary serum protein involved in binding and transport of drugs and as such has the potential to affect, or be affected by, certain medications. Of current relevance are antibody-based inhibitors of the neonatal Fc receptor (FcRn), several of which are under clinical development to treat immunoglobulin G (IgG)-mediated autoimmune disorders; some have been shown to decrease SA concentration. FcRn acts as a homeostatic regulator of SA by rescuing it, as well as IgG, from intracellular degradation via a common cellular recycling mechanism. Greater clinical understanding of the multifunctional nature of SA and the potential clinical impact of decreased SA are needed; in particular, the potential for certain treatments to reduce SA concentration, which may affect efficacy and toxicity of medications and disease progression.


Assuntos
Doenças Autoimunes , Imunoglobulina G , Doenças Autoimunes/tratamento farmacológico , Homeostase , Humanos , Imunoglobulina G/metabolismo , Recém-Nascido , Receptores Fc , Albumina Sérica/metabolismo
7.
Proc Natl Acad Sci U S A ; 105(34): 12319-24, 2008 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-18713856

RESUMO

Furin is a proprotein convertase which activates a variety of regulatory proteins in the constitutive exocytic and endocytic pathway. The effect of genetic ablation of fur was studied in the endocrine pancreas to define its physiological function in the regulated secretory pathway. Pdx1-Cre/loxP furin KO mice show decreased secretion of insulin and impaired processing of known PC2 substrates like proPC2 and proinsulin II. Both secretion and PC2 activity depend on granule acidification, which was demonstrated to be significantly decreased in furin-deficient beta cells by using the acidotrophic agent 3-(2,4-dinitroanilino)-3'amino-N-methyldipropylamine (DAMP). Ac45, an accessory subunit of the proton pump V-ATPase, was investigated as a candidate substrate. Ac45 is highly expressed in islets of Langerhans and furin was able to cleave Ac45 ex vivo. Furthermore, the exact cleavage site was determined. In addition, reduced regulated secretion and proinsulin II processing could be obtained in the insulinoma cell line betaTC3 by downregulation of either furin or Ac45. Together, these data establish an important role for furin in regulated secretion, particularly in intragranular acidification most likely due to impaired processing of Ac45.


Assuntos
Grânulos Citoplasmáticos/metabolismo , Furina/fisiologia , Ilhotas Pancreáticas/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Furina/deficiência , Furina/metabolismo , Concentração de Íons de Hidrogênio , Insulina/metabolismo , Secreção de Insulina , Insulinoma , Ilhotas Pancreáticas/ultraestrutura , Camundongos , Camundongos Knockout , Especificidade por Substrato
9.
Nat Genet ; 43(9): 908-12, 2011 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-21841782

RESUMO

A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-κB activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Cisteína Endopeptidases/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células Mieloides/enzimologia , Animais , Artrite Reumatoide/sangue , Citocinas/sangue , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Fator de Necrose Tumoral alfa/metabolismo
10.
J Biol Chem ; 279(51): 53442-50, 2004 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-15471862

RESUMO

Furin is an endoprotease of the family of mammalian proprotein convertases and is involved in the activation of a large variety of regulatory proteins by cleavage at basic motifs. A large number of substrates have been attributed to furin on the basis of in vitro and ex vivo data. However, no physiological substrates have been confirmed directly in a mammalian model system, and early embryonic lethality of a furin knock-out mouse model has precluded in vivo verification of most candidate substrates. Here, we report the generation and characterization of an interferon inducible Mx-Cre/loxP furin knock-out mouse model. Induction resulted in near-complete ablation of the floxed fur exon in liver. In sharp contrast with the general furin knock-out mouse model, no obvious adverse effects were observed in the transgenic mice after induction. Histological analysis of the liver did not reveal any overt deviations from normal morphology. Analysis of candidate substrates in liver revealed complete redundancy for the processing of the insulin receptor. Variable degrees of redundancy were observed for the processing of albumin, alpha(5) integrin, lipoprotein receptor-related protein, vitronectin and alpha(1)-microglobulin/bikunin. None of the tested substrates displayed a complete block of processing. The absence of a severe phenotype raises the possibility of using furin as a local therapeutic target in the treatment of pathologies like cancer and viral infections, although the observed redundancy may require combination therapy or the development of a more broad spectrum convertase inhibitor.


Assuntos
Furina/química , Fígado/metabolismo , Pró-Proteína Convertases/química , Albuminas/metabolismo , Alelos , alfa-Globulinas/metabolismo , Motivos de Aminoácidos , Animais , Northern Blotting , Western Blotting , Primers do DNA/química , Eletroforese em Gel de Poliacrilamida , Furina/metabolismo , Furina/fisiologia , Genótipo , Imuno-Histoquímica , Integrina alfa5/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Genéticos , Neoplasias/metabolismo , Fenótipo , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Receptores de LDL/metabolismo , Proteínas Recombinantes/metabolismo , Recombinação Genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade por Substrato , Transgenes , Inibidor da Tripsina de Soja de Kunitz/metabolismo , Vitronectina/metabolismo
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