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1.
Immunity ; 56(8): 1939-1954.e12, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37442134

RESUMO

Lung infection during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin-I-converting enzyme 2 (ACE2) receptor induces a cytokine storm. However, the precise mechanisms involved in severe COVID-19 pneumonia are unknown. Here, we showed that interleukin-10 (IL-10) induced the expression of ACE2 in normal alveolar macrophages, causing them to become vectors for SARS-CoV-2. The inhibition of this system in hamster models attenuated SARS-CoV-2 pathogenicity. Genome-wide association and quantitative trait locus analyses identified a IFNAR2-IL10RB readthrough transcript, COVID-19 infectivity-enhancing dual receptor (CiDRE), which was highly expressed in patients harboring COVID-19 risk variants at the IFNAR2 locus. We showed that CiDRE exerted synergistic effects via the IL-10-ACE2 axis in alveolar macrophages and functioned as a decoy receptor for type I interferons. Collectively, our data show that high IL-10 and CiDRE expression are potential risk factors for severe COVID-19. Thus, IL-10R and CiDRE inhibitors might be useful COVID-19 therapies.


Assuntos
COVID-19 , Humanos , COVID-19/genética , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Interleucina-10/genética , Macrófagos Alveolares/metabolismo , Estudo de Associação Genômica Ampla , Peptidil Dipeptidase A/metabolismo
2.
Cell ; 153(5): 1036-49, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23706741

RESUMO

Regnase-1 (also known as Zc3h12a and MCPIP1) is an RNase that destabilizes a set of mRNAs, including Il6 and Il12b, through cleavage of their 3' UTRs. Although Regnase-1 inactivation leads to development of an autoimmune disease characterized by T cell activation and hyperimmunoglobulinemia in mice, the mechanism of Regnase-1-mediated immune regulation has remained unclear. We show that Regnase-1 is essential for preventing aberrant effector CD4(+) T cell generation cell autonomously. Moreover, in T cells, Regnase-1 regulates the mRNAs of a set of genes, including c-Rel, Ox40, and Il2, through cleavage of their 3' UTRs. Interestingly, T cell receptor (TCR) stimulation leads to cleavage of Regnase-1 at R111 by Malt1/paracaspase, freeing T cells from Regnase-1-mediated suppression. Furthermore, Malt1 protease activity is critical for controlling the mRNA stability of T cell effector genes. Collectively, these results indicate that dynamic control of Regnase-1 expression in T cells is critical for controlling T cell activation.


Assuntos
Caspases/metabolismo , Ativação Linfocitária , Proteínas de Neoplasias/metabolismo , Ribonucleases/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Doenças Autoimunes/imunologia , Humanos , Interleucina-2/genética , Células Jurkat , Glicoproteínas de Membrana/genética , Camundongos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Ligante OX40 , Proteínas Proto-Oncogênicas c-rel/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Fatores de Necrose Tumoral/genética
3.
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34168078

RESUMO

Chronic obstructive pulmonary disease (COPD/emphysema) is a life-threatening disorder and there are few effective therapies. Cigarette smoke-induced oxidative stress, airway inflammation, and apoptosis of lung cells have been reported to be involved in the pathogenesis of COPD/emphysema and lead to alveolar septal destruction. Here we show that the expression level of FCH and double SH3 domains 1 (FCHSD1) was drastically increased in mice in response to elastase instillation, an experimental model of COPD. FCHSD1 is a member of the F-BAR family with two SH3 domains. We found that Fchsd1 knockout (Fchsd1-/-) mice were protected against airspace enlargement induced by elastase. Elastase-instilled lungs of Fchsd1-/- mice showed reduced inflammation and apoptosis compared with WT mice. We also found that elastase-induced reduction of Sirtuin 1 (SIRT1) levels, a histone deacetylase reported to protect against emphysema, was attenuated in the lungs of Fchsd1-/- mice. Furthermore, FCHSD1 deficiency enhanced nuclear translocation of nuclear factor-like 2 (NRF2), a redox-sensitive transcription factor, following H2O2 stimulation. Conversely, Fchsd1 overexpression inhibited NRF2 nuclear translocation and increased the reduction of SIRT1 levels. Notably, FCHSD1 interacted with NRF2 and SNX9. Our results show that FCHSD1 forms a multicomplex with NRF2 and SNX9 in the cytosol that prevents NRF2 from translocating to the nucleus. We propose that FCHSD1 promotes initiation of emphysema development by inhibiting nuclear translocation of NRF2, which leads to down-regulation of SIRT1.


Assuntos
Proteínas de Membrana/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Apoptose , Morte Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Peróxido de Hidrogênio/toxicidade , Carioferinas , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Elastase Pancreática , Pneumonia/complicações , Pneumonia/patologia , Ligação Proteica/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/complicações , Enfisema Pulmonar/prevenção & controle , Sirtuína 1/metabolismo , Nexinas de Classificação/metabolismo
4.
J Anesth ; 38(1): 44-56, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37910301

RESUMO

PURPOSE: The role of the nitric oxide synthases (NOSs) system in cerebral infarction has been examined in pharmacological studies with non-selective NOSs inhibitors. However, due to the non-specificity of the non-selective NOSs inhibitors, its role remains to be fully elucidated. We addressed this issue in mice in which neuronal, inducible, and endothelial NOS isoforms were completely disrupted. METHODS AND RESULTS: We newly generated mice lacking all three NOSs by crossbreeding each single NOS-/- mouse. In the male, cerebral infarct size at 24 h after middle cerebral artery occlusion (MCAO) was significantly smaller in the triple n/i/eNOSs-/- genotype as compared with wild-type genotype. Neurological deficit score and mortality rate were also significantly lower in the triple n/i/eNOSs-/- than in the WT genotype. In contrast, in the female, there was no significant difference in the cerebral infarct size in the two genotypes. In the male triple n/i/eNOSs-/- genotype, orchiectomy significantly increased the cerebral infarct size, and in the orchiectomized male triple n/i/eNOSs-/- genotype, treatment with testosterone significantly reduced it. Cyclopaedic and quantitative comparisons of mRNA expression levels in cerebral infarct lesions between the male wild-type and triple n/i/eNOSs-/- genotypes at 1 h after MCAO revealed significant involvements of decreased oxidative stress and mitigated mitochondrial dysfunction in the alleviated cerebral infarction in the male triple n/i/eNOSs-/- genotype. CONCLUSIONS: These results provide the first evidence that the NOSs system exerts a deleterious effect against acute ischemic brain injury in the male.


Assuntos
Infarto da Artéria Cerebral Média , Óxido Nítrico Sintase , Camundongos , Masculino , Feminino , Animais , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Isoformas de Proteínas/metabolismo , Estresse Oxidativo , Óxido Nítrico , Camundongos Knockout
5.
Nat Immunol ; 12(12): 1167-75, 2011 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-22037600

RESUMO

Toll-like receptor (TLR) signaling activates the inhibitor of transcription factor NF-κB (IκB) kinase (IKK) complex, which governs NF-κB-mediated transcription during inflammation. The RNase regnase-1 serves a critical role in preventing autoimmunity by controlling the stability of mRNAs that encode cytokines. Here we show that the IKK complex controlled the stability of mRNA for interleukin 6 (IL-6) by phosphorylating regnase-1 in response to stimulation via the IL-1 receptor (IL-1R) or TLR. Phosphorylated regnase-1 underwent ubiquitination and degradation. Regnase-1 was reexpressed in IL-1R- or TLR-activated cells after a period of lower expression. Regnase-1 mRNA was negatively regulated by regnase-1 itself via a stem-loop region present in the regnase-1 3' untranslated region. Our data demonstrate that the IKK complex phosphorylates not only IκBα, thereby activating transcription, but also regnase-1, thereby releasing a 'brake' on IL-6 mRNA expression.


Assuntos
Citocinas/genética , Quinase I-kappa B/metabolismo , Estabilidade de RNA , RNA Mensageiro/metabolismo , Receptores de Interleucina-1/metabolismo , Ribonucleases/metabolismo , Receptores Toll-Like/metabolismo , Motivos de Aminoácidos , Animais , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-6/genética , Camundongos , Camundongos Knockout , Modelos Biológicos , Ligação Proteica
6.
Proc Natl Acad Sci U S A ; 114(35): E7331-E7340, 2017 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-28808017

RESUMO

The development of effective treatments against cancers is urgently needed, and the accumulation of CD8+ T cells within tumors is especially important for cancer prognosis. Although their mechanisms are still largely unknown, growing evidence has indicated that innate immune cells have important effects on cancer progression through the production of various cytokines. Here, we found that basic leucine zipper transcription factor ATF-like 2 (Batf2) has an antitumor effect. An s.c. inoculated tumor model produced fewer IL-12 p40+ macrophages and activated CD8+ T cells within the tumors of Batf2-/- mice compared with WT mice. In vitro studies also revealed that the IL-12 p40 expression was significantly lower in Batf2-/- macrophages following their stimulation by toll-like receptor ligands, such as R848. Additionally, we found that BATF2 interacts with p50/p65 and promotes IL-12 p40 expression. In conclusion, Batf2 has an antitumor effect through the up-regulation of IL-12 p40 in tumor-associated macrophages, which eventually induces CD8+ T-cell activation and accumulation within the tumor.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Antineoplásicos/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Interleucina-12/metabolismo , Interleucina-12/fisiologia , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Subunidades Proteicas/metabolismo , Células RAW 264.7 , Receptor 7 Toll-Like/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/farmacologia , Regulação para Cima
7.
Int Immunol ; 30(2): 69-78, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29528433

RESUMO

Schlafen-8 (Slfn8) is a member of the Schlafen family of proteins, which harbor helicase domains and are induced by LPS and interferons. It has been reported that the Schlafen family are involved in various cellular functions, including proliferation, differentiation and regulation of virus replication. Slfn8 has been implicated in T-cell differentiation in the thymus. However, the roles of Slfn8 in the immune system remains unclear. In this study, we generated Slfn8 knockout mice (Slfn8-/-) and investigated the immunological role of Slfn8 using the T-cell-mediated autoimmune model experimental autoimmune encephalomyelitis (EAE). We found that the clinical score was reduced in Slfn8-/- mice. IL-6 and IL-17A cytokine production, which are associated with EAE onset and progression, were decreased in the lymph nodes of Slfn8-/- mice. Immune cell populations in Slfn8-/- mice, including macrophages, neutrophils, T cells and B cells, did not reveal significant differences compared with wild-type mice. In vitro activation of Slfn8-/- T cells in response to TCR stimulation also did not reveal significant differences. To confirm the involvement of non-hematopoietic cells, we isolated CD45- CD31+ endothelial cells and CD45-CD31- gp38+ fibroblastic reticular cells by FACS sorting. We showed that the levels of IL-6 and Slfn8 mRNA in CD45- CD31+ endothelial cells were increased after EAE induction. In contrast, the level of IL-6 mRNA after EAE induction was markedly decreased in CD31+ endothelial cells from Slfn8-/- mice. These results indicate that Slfn8 may play a role in EAE by regulating inflammation in endothelial cells.


Assuntos
Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Células Endoteliais/metabolismo , Animais , Biomarcadores , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Imunidade Inata , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/efeitos adversos , Fragmentos de Peptídeos/efeitos adversos , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/metabolismo
8.
Proc Natl Acad Sci U S A ; 111(15): 5646-51, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24706898

RESUMO

The RIG-I-like receptors, retinoic acid inducible gene-1 (RIG-I), melanoma differentiation-associated protein 5, and laboratory of genetics and physiology-2, are cytoplasmic sensors for RNA viruses that mediate the antiviral innate immune responses. We demonstrate that really interesting new gene-finger domain- and K homology domain-containing MEX3C regulates RIG-I function. MEX3C colocalizes with RIG-I in the stress granules of virally infected cells, and its overexpression causes the lysine-63-linked ubiquitination of RIG-I and activates IFN-ß promoter. Embryonic fibroblast cells, macrophages, and conventional dendritic cells derived from Mex3c-deficient mice showed defective production of type I IFN after infection with RNA viruses that are recognized by RIG-I. These results demonstrate that MEX3C is an E3 ubiquitin ligase that modifies RIG-I in stress granules and plays a critical role in eliciting antiviral immune responses.


Assuntos
Imunidade Inata/imunologia , Proteínas de Ligação a RNA/imunologia , Receptores do Ácido Retinoico/imunologia , Viroses/imunologia , Animais , Citocinas/biossíntese , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Células HEK293 , Humanos , Immunoblotting , Imunoprecipitação , Luciferases , Camundongos , Camundongos Knockout , Mutagênese Sítio-Dirigida , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores do Ácido Retinoico/metabolismo , Ubiquitinação
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