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1.
Eur J Immunol ; 51(5): 1182-1194, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33521935

RESUMO

Stringent regulation of the inflammatory response is crucial for normal tissue regeneration. Here, we analyzed the role of Toll-like receptor 3 (TLR3) in pancreatic regeneration after acute pancreatitis (AP). AP was induced by caerulein treatment in mice with global TLR3 deficiency (TLR3OFF ) or in mice re-expressing TLR3 exclusively in the myeloid cell lineage (TLR3Mye ). Compared to WT mice, TLR3OFF mice had a markedly increased formation of acinar-to-ductal metaplasia (ADM) that persisted until day 7 after initiation of AP. Pancreatic tissue of WT mice was completely regenerated after 5 days with no detectable ADM structures. The enhancing effect of TLR3-deficiency on ADM formation was closely linked with an increased and prolonged accumulation of macrophages in pancreata of TLR3OFF mice. Importantly, the phenotype of TLR3OFF mice was rescued in TLR3Mye mice, demonstrating the causative role of myeloid cell selective TLR3 signaling. Moreover, in vitro stimulation of macrophages through TLR3 initiated cell death by a caspase-8-associated mechanism. Therefore, these findings provide evidence that TLR3 signaling in myeloid cells is sufficient to limit inflammation and ADM formation and to promote regeneration after AP. Notably, resolution of inflammation after AP was associated with macrophage sensitivity to TLR3-mediated cell death.


Assuntos
Expressão Gênica , Células Mieloides/metabolismo , Pancreatite/genética , Pancreatite/metabolismo , Receptor 3 Toll-Like/genética , Doença Aguda , Animais , Biomarcadores , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , Pancreatite/imunologia , Pancreatite/patologia , Regeneração/genética , Transdução de Sinais , Receptor 3 Toll-Like/metabolismo
2.
Sci Rep ; 8(1): 12271, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115978

RESUMO

Stimulation of cytosolic nucleic acid sensors of innate immunity by pathogen-derived nucleic acids is important for antimicrobial defence, but stimulation through self-derived nucleic acids may contribute to autoinflammation and cancer. DNA sensing in the cytosol requires the stimulator of interferon genes (STING), while cytosolic RNA sensors use mitochondrial antiviral-signalling protein (MAVS). In a murine model of two-thirds hepatectomy, combined deficiency of MAVS and STING resulted in strongly impaired hepatocyte proliferation and delayed recovery of liver mass. Whereas lack of MAVS and STING did not influence upregulation of the G1-phase cyclins D1 and E1, it substantially reduced the hyperphosphorylation of retinoblastoma protein, attenuated the activation of cyclin-dependent kinase (CDK)-2, delayed upregulation of CDK1 and cyclins A2 and B1, and impaired S-phase entry of hepatocytes. Mechanistically, lack of cytosolic nucleic acid sensors strongly upregulated the anti-proliferative mediators TGF-ß2 and activin A, which was associated with an increased expression of the cell cycle inhibitors p15 and p21. Partial hepatectomy was followed by the release of exosomes with abundant nucleic acid cargo, which may provide ligands for the MAVS and STING pathways. Together, these findings identify a previously unrecognised function of cytosolic nucleic acid sensors of innate immunity for promoting liver regeneration.


Assuntos
Citosol/metabolismo , DNA/metabolismo , Hepatectomia , Imunidade Inata , Regeneração Hepática/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Ciclo Celular , Proliferação de Células , Hepatócitos/citologia , Hepatócitos/metabolismo , Interleucina-6/biossíntese , Proteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Regulação para Cima
3.
J Immunol ; 188(12): 5833-7, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22586041

RESUMO

Although global MyD88 deficiency attenuates lethal inflammation in sepsis, cell-specific functions of MyD88 remain largely unknown. Using mice with selective expression of MyD88 in myeloid cells (Myd88(MYEL)), we show that, during polymicrobial septic peritonitis, both myeloid and nonmyeloid cells contribute to systemic inflammation, whereas myeloid cell MyD88 was sufficient to fully establish the peritoneal cytokine response. Importantly, Myd88(MYEL) mice developed markedly aggravated liver injury that was linked to impaired upregulation of cellular inhibitor of apoptosis protein 2 and an excessive production of TNF-α. Upregulation of inducible cAMP early repressor (ICER), a known transcriptional repressor of the Tnfa gene, was impaired in Myd88(MYEL) mice. Moreover, Myd88(MYEL) mice showed enhanced transcription of the Tnfa gene and an excessive production of CCL3, which is also negatively regulated by ICER, but they had normal levels of CXCL1, which is expressed in an ICER-independent manner. Together, these findings suggest a novel protective role for nonmyeloid cell MyD88 in attenuating liver injury during septic peritonitis.


Assuntos
Fator 88 de Diferenciação Mieloide/imunologia , Peritonite/imunologia , Sepse/imunologia , Animais , Modulador de Elemento de Resposta do AMP Cíclico/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Inflamação/imunologia , Inflamação/metabolismo , Proteínas Inibidoras de Apoptose/imunologia , Proteínas Inibidoras de Apoptose/metabolismo , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Células Mieloides/imunologia , Células Mieloides/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Peritonite/metabolismo , Peritonite/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sepse/metabolismo , Sepse/patologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
4.
Immunobiology ; 217(6): 616-21, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22204813

RESUMO

It has been postulated that an early systemic inflammatory response syndrome (SIRS) and a subsequent compensatory anti-inflammatory response syndrome (CARS) occur sequentially in sepsis. Co-existence of both is referred to as mixed antagonist response syndrome (MARS). Pro- and anti-inflammatory cytokine production was investigated in patients with postoperative sepsis, a murine peritonitis model and in vitro to further delineate the interaction of hyper- and hypo-inflammation in sepsis. IL-6 and IL-10 were measured in serum samples from 80 patients on d1 and d2 of postoperative sepsis and were similarly determined at various time points after induction of septic peritonitis in mice. Cytokine production of RAW264 macrophages was stimulated in vitro using TLR agonists. IL-6 and IL-10 were measured in supernatants. All cytokine measurements were performed by ELISA. In patients, the initial phase of the immune response to sepsis was characterized by a concomitant elevation of serum IL-6 and IL-10 levels. IL-10 levels were correlated with IL-6 levels in an exponential manner (p<0.001), which could be confirmed in a mouse model of septic peritonitis. In vitro experiments revealed that the observed exponential correlation may occur as function of TLR signaling intensity. Early postoperative sepsis seems to be characterized by a primary MARS. Sepsis severity was positively correlated with a disproportionate elevation of the anti-inflammatory response relative to the pro-inflammatory response, a pattern reminiscent of TLR-driven responses. Detailed characterization of immune responses in sepsis may help to direct standard therapies and to develop effective immunomodulatory strategies.


Assuntos
Macrófagos/efeitos dos fármacos , Peritonite/imunologia , Complicações Pós-Operatórias/imunologia , Sepse/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Receptores Toll-Like/agonistas , Idoso , Animais , Linhagem Celular , Feminino , Humanos , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Peritonite/metabolismo , Sepse/complicações , Sepse/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Síndrome de Resposta Inflamatória Sistêmica/complicações , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Receptores Toll-Like/imunologia
5.
J Immunol ; 184(10): 5842-8, 2010 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-20375303

RESUMO

The adapter protein TRIF mediates signal transduction through TLR3 and TLR4, inducing production of type I IFNs and inflammatory cytokines. The present study investigates the mechanisms by which TRIF signaling controls TNF-alpha biosynthesis. We provide evidence that, in LPS-stimulated murine dendritic cells, TRIF stimulates TNF-alpha biosynthesis selectively at the posttranscriptional level by promoting mRNA translation. In the absence of functional TRIF, the production of TNF-alpha protein was severely impaired, whereas TNF-alpha mRNA levels and stability, as well as transcriptional activity of the Tnfa gene, were not affected. Similarly, TRIF was required for production of LPS-induced TNF-alpha protein, but not of mRNA, in bone marrow-derived macrophages. In peritoneal macrophages, however, TRIF was also required for normal induction of TNF-alpha mRNA, suggesting cell type-related functions of TRIF. The influence of TRIF on dendritic cell TNF-alpha production was independent of type I IFNs. TRIF was required for prolonged activation of MAPKs in LPS-stimulated dendritic cells but was dispensable for the activation of NF-kappaB. Inhibition of late p38 activity attenuated LPS-stimulated elevation of TNF-alpha protein but not mRNA levels. The p38 effector kinase MK2 was directly activated through the TRIF pathway of TLR4. Importantly, stimulation of Mk2(-/-) cells through TLR3 or TLR4 severely impaired TNF-alpha protein production but did not affect TNF-alpha mRNA induction. Together, these results indicate that the TRIF signaling pathway promotes TNF-alpha mRNA translation through activation of the protein kinase MK2.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Biossíntese de Proteínas/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Células da Medula Óssea/enzimologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células Cultivadas , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/fisiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
6.
J Biol Chem ; 285(6): 3525-3531, 2010 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-20018859

RESUMO

Sensory nerves may dampen inflammatory processes through the release of the neuropeptide calcitonin gene-related peptide (CGRP). CGRP mediates immunosuppressive activities through up-regulation of interleukin-10 or, alternatively, through an interleukin-10-independent pathway that is associated with rapid induction of the transcriptional inducible cAMP early repressor (ICER). In this work, we further investigated the molecular mechanisms of immune modulation by CGRP. Using TLR2-stimulated dendritic cells, we show that inhibition of tumor necrosis factor-alpha production by CGRP is dependent on up-regulation of endogenous ICER. Dendritic cell expression of ICER was selectively induced by CGRP and elevation of cellular cAMP levels but not by numerous pro- and anti-inflammatory cytokines. Treatment of dendritic cells with CGRP did not interfere with the induction of Tnfa gene expression but caused premature repression of TLR2-induced transcriptional activity. ATF-2 was rapidly phosphorylated and recruited to the Tnfa promoter following ligation of TLR2. Concomitant administration of CGRP completely prevented binding of ATF-2 to the Tnfa promoter, whereas recruitment of ICER was markedly elevated. In contrast, CGRP did not influence TLR2-stimulated binding of NF-kappaB p65. Together, these results are consistent with a model suggesting that CGRP causes rapid up-regulation of ICER, which in turn competes with ATF-2 for binding to the Tnfa promoter, leading to repression of gene expression.


Assuntos
Fator 2 Ativador da Transcrição/genética , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Células Dendríticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Receptor 2 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator 2 Ativador da Transcrição/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Imunoprecipitação da Cromatina , AMP Cíclico/metabolismo , Modulador de Elemento de Resposta do AMP Cíclico/genética , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Ensaio de Imunoadsorção Enzimática , Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição RelA/metabolismo , Transcrição Gênica/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
7.
J Immunol ; 179(1): 607-15, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17579082

RESUMO

Communication between the nervous and immune systems involves the release of neuropeptides, such as calcitonin gene-related peptide (CGRP), from sensory nerves during inflammation. CGRP may inhibit the activities of both innate and adaptive immune cells, but the molecular pathways underlying this function are largely unknown. In this study, we identify CGRP as a potent inhibitor of TLR-stimulated production of inflammatory mediators, such as TNF-alpha and CCL4, by murine dendritic cells. Inhibition of TLR responses was independent of IL-10 and did not involve perturbation of canonical TLR signaling, including activation of MAPK and NF-kappaB. Instead, the inhibitory activity of CGRP was mediated by the cAMP/protein kinase A pathway leading to rapid up-regulation of the transcriptional repressor, inducible cAMP early repressor (ICER). Ectopically expressed ICER directly repressed the LPS-stimulated activity of a synthetic Tnf promoter, as well as TNF-alpha protein production driven by the endogenous promoter. Inhibition of dendritic cell gene expression by CGRP was associated with the presence of a composite cAMP response element/kappaB promoter element. In a murine model of endotoxemia, CGRP markedly attenuated serum TNF-alpha levels, and this effect was associated with the up-regulation of ICER. Together, these results establish a novel pathway for the negative regulation of TLR responses through the nervous system that critically involves induction of the transcriptional repressor ICER by the neuropeptide CGRP.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Modulador de Elemento de Resposta do AMP Cíclico/fisiologia , Regulação para Baixo/imunologia , Proteínas Repressoras/fisiologia , Receptores Toll-Like/antagonistas & inibidores , Receptores Toll-Like/fisiologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Linhagem Celular , AMP Cíclico/biossíntese , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Endotoxemia/imunologia , Feminino , Humanos , Lipopolissacarídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/imunologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Transcrição Gênica , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética
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