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1.
Nat Commun ; 14(1): 3236, 2023 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-37270534

RESUMO

Excessive TGF-ß signaling and mitochondrial dysfunction fuel chronic kidney disease (CKD) progression. However, inhibiting TGF-ß failed to impede CKD in humans. The proximal tubule (PT), the most vulnerable renal segment, is packed with giant mitochondria and injured PT is pivotal in CKD progression. How TGF-ß signaling affects PT mitochondria in CKD remained unknown. Here, we combine spatial transcriptomics and bulk RNAseq with biochemical analyses to depict the role of TGF-ß signaling on PT mitochondrial homeostasis and tubulo-interstitial interactions in CKD. Male mice carrying specific deletion of Tgfbr2 in the PT have increased mitochondrial injury and exacerbated Th1 immune response in the aristolochic acid model of CKD, partly, through impaired complex I expression and mitochondrial quality control associated with a metabolic rewiring toward aerobic glycolysis in the PT cells. Injured S3T2 PT cells are identified as the main mediators of the maladaptive macrophage/dendritic cell activation in the absence of Tgfbr2. snRNAseq database analyses confirm decreased TGF-ß receptors and a metabolic deregulation in the PT of CKD patients. This study describes the role of TGF-ß signaling in PT mitochondrial homeostasis and inflammation in CKD, suggesting potential therapeutic targets that might be used to mitigate CKD progression.


Assuntos
Insuficiência Renal Crônica , Transdução de Sinais , Humanos , Masculino , Camundongos , Animais , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Transdução de Sinais/fisiologia , Insuficiência Renal Crônica/complicações , Rim/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Mitocôndrias/metabolismo , Inflamação/metabolismo , Fibrose
2.
Evolution ; 76(8): 1660-1673, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35696526

RESUMO

Because of ongoing climate change, populations of organisms are being subjected to stressful temperatures more often. This is especially problematic for ectothermic organisms, which are likely to be more sensitive to changes in temperature. Therefore, we need to know if ectotherms have adapted to environmental temperature and, if so, what are the evolutionary mechanisms behind such adaptation. Here, we use the nematode Pristionchus pacificus as a case study to investigate thermal adaptation on the Indian Ocean island of La Réunion, which experiences a range of temperatures from coast to summit. We study the evolution of high-temperature tolerance by constructing a phylogenetic tree of strains collected from many different thermal niches. We show that populations of P. pacificus at low altitudes have higher fertility at warmer temperatures. Most likely, this phenotype has arisen recently and at least twice independently, consistent with parallel evolution. We also studied low-temperature tolerance and showed that populations from high altitudes have increased their fertility at cooler temperatures. Together, these data indicate that P. pacificus strains on La Réunion are subject to divergent selection, adapting to hot and cold niches at the coast and summit of the volcano. Precisely defining these thermal niches provides essential information for models that predict the impact of future climate change on these populations.


Assuntos
Nematoides , Rabditídios , Adaptação Fisiológica , Altitude , Animais , Nematoides/genética , Filogenia , Rabditídios/genética , Temperatura
3.
Sci Signal ; 14(674)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33727336

RESUMO

The nucleoside adenosine accumulates extracellularly in solid tumors and inhibits CD8+ T cells by activating adenosine receptors. The cytokine interleukin-7 (IL-7), which is produced by various tissues and tumors, promotes the survival and maintenance of T cells. Adenosine and IL-7 signaling are being clinically targeted separately or in combination with other therapies for solid tumor indications. Here, we found that IL-7 signaling promoted the accumulation of tumor-associated CD8+ T cells, in part, by preventing adenosine-mediated immunosuppression. Inhibition of the transcription factor FoxO1 downstream of IL-7 receptor signaling was important for protecting CD8+ T cells from suppression by adenosine. These findings have implications for the development of new approaches for cancer immunotherapies that target the adenosine pathway.


Assuntos
Adenosina/farmacologia , Linfócitos T CD8-Positivos , Terapia de Imunossupressão , Interleucina-7 , Animais , Tolerância Imunológica , Camundongos
4.
J Allergy Clin Immunol ; 147(6): 2118-2133.e3, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33440200

RESUMO

BACKGROUND: Steroid-resistant asthma is often characterized by high levels of neutrophils and mixed TH2/TH17 immune profiles. Indeed, neutrophils are key drivers of chronic lung inflammation in multiple respiratory diseases. Their numbers correlate strongly with disease severity, and their presence is often associated with exacerbation of chronic lung inflammation. OBJECTIVE: What factors drive development of neutrophil-mediated chronic lung disease remains largely unknown, and we sought to study the role of GM-CSF as a potential regulator in chronic asthma. METHODS: Different experimental animal models of chronic asthma were used in combination with alveolar macrophage-reconstitution of global GM-CSF receptor knockout mice as well as cell-type-specific knockout animals to elucidate the role of GM-CSF signaling in chronic airway inflammation. RESULTS: We identify GM-CSF signaling as a critical factor regulating pulmonary accumulation of neutrophils. We show that although being not required for intrinsically regulating neutrophil migration, GM-CSF controls lung dendritic cell function, which in turn promotes T-cell-dependent recruitment of neutrophils to the airways. We demonstrate that GM-CSF regulates lung dendritic cell antigen uptake, transport, and TH2/TH17 cell priming in an intrinsic fashion, which in turn drives pulmonary granulocyte recruitment and contributes to development of airway hyperresponsiveness in chronic disease. CONCLUSIONS: We identify GM-CSF as a potentially novel therapeutic target in chronic lung inflammation, describing a GM-CSF-dependent lung conventional dendritic cell-T-cell-neutrophil axis that drives chronic lung disease.


Assuntos
Asma/etiologia , Asma/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Biomarcadores , Comunicação Celular , Doença Crônica , Modelos Animais de Doenças , Suscetibilidade a Doenças , Contagem de Linfócitos , Camundongos , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Índice de Gravidade de Doença
5.
J Immunol ; 203(12): 3247-3255, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31722989

RESUMO

Extracellular adenosine accumulates in tumors and causes suppression of immune cells. Suppressive adenosine signaling is achieved through adenosine A2A and A2B receptors, which are Gs coupled, and their activation elevates cAMP levels. Gs-coupled GPCR signaling causes cAMP accumulation, which plays an anti-inflammatory role in immune cells. Protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) are two intracellular receptors of cAMP. In this study we showed that adenosine receptor signaling polarizes activated murine dendritic cells (DCs) into a tumor-promoting suppressive phenotype. Adenosine receptor signaling activates cAMP pathway and upregulates the negative regulators of NF-κB but does not influence phosphorylation of immediate inflammatory signaling molecules downstream of TLR signaling. Pharmacologic activation of both PKA and Epac pathways by specific cAMP analogues phenocopied the effects of adenosine signaling on murine DCs, such as suppression of proinflammatory cytokines, elevation of anti-inflammatory IL-10, increased expression of regulators of NF-κB pathway, and finally suppression of T cell activation. Inhibition of effector cytokine, IL-12p40 production, and increased immunosuppressive IL-10 production by adenosine signaling is significantly reversed only when both PKA and Epac pathways were inhibited together. Adenosine signaling increased IL-10 secretion while decreasing IL-12p40 secretion in human monocyte-derived DCs. Stimulation of both PKA and Epac pathways also caused combinatorial effects in regulation of IL-12p40 secretion in human monocyte-derived DCs. Interestingly, PKA signaling alone caused similar increase in IL-10 secretion to that of adenosine signaling in human monocyte-derived DCs. Our data suggest adenosine/cAMP signaling targets both PKA/Epac pathways to fully differentiate DCs into a suppressive phenotype.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fenótipo , Receptores Purinérgicos P1/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , AMP Cíclico/metabolismo , Suscetibilidade a Doenças , Feminino , Imunomodulação , Camundongos , Fosforilação , Transdução de Sinais/efeitos dos fármacos
6.
J Allergy Clin Immunol ; 143(4): 1513-1524.e2, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30244025

RESUMO

BACKGROUND: Eosinophils are a therapeutic target in asthmatic patients, and GM-CSF has been suggested to control various aspects of eosinophil biology, including development, function, and survival. However, to date, the role of GM-CSF signaling in eosinophils in vivo is largely unclear. OBJECTIVE: We sought to elucidate the role of GM-CSF signaling in asthmatic inflammation. METHODS: Wild-type and GM-CSF receptor α (Csf2ra)-deficient mice reconstituted with Csf2ra-proficient alveolar macrophages were subjected to different models of airway inflammation to evaluate the effect of GM-CSF signaling deficiency on asthmatic inflammation in general and on eosinophils in particular. RESULTS: We demonstrate that GM-CSF signaling, although being largely dispensable for eosinophil development at steady state, intrinsically promotes accumulation of eosinophils in the lung during allergic airway inflammation. In contrast, chitin-induced eosinophil accumulation in the peritoneal cavity occurs independent of GM-CSF, indicating organ specificity. We show that GM-CSF induces chemokinesis and promotes eosinophil survival in vitro, which likely contribute to eosinophil accumulation in the airways in vivo. CONCLUSION: GM-CSF intrinsically promotes eosinophil accumulation in the setting of pulmonary allergic inflammation.


Assuntos
Eosinófilos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Eosinofilia Pulmonar/imunologia , Hipersensibilidade Respiratória/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/deficiência
7.
Clin Cancer Res ; 24(8): 1987-2001, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29386221

RESUMO

Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance.Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance.Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivoConclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987-2001. ©2018 AACR.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Resistencia a Medicamentos Antineoplásicos , Receptores de Estrogênio/metabolismo , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Tamoxifeno/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Modelos Biológicos , Inibidores da Fosfodiesterase 4/farmacologia , Estresse Fisiológico/genética , Tamoxifeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Neurochem Res ; 40(3): 600-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25555707

RESUMO

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, which is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. There is a growing consensus that mitochondrial dysfunction and oxidative stress play a crucial role in PD pathogenesis. Sirtuin3 (SIRT3) is the major mitochondria NAD(+)-dependent deacetylase that acts as a regulator of mitochondrial protein function; it is essential for maintaining mitochondrial integrity. Although SIRT3 was reported to have anti-oxidative stress activity in an in vitro study, there is no explicit in vivo evidence for the involvement of SIRT3 in the etiology of PD. The present study shows that SIRT3 null mice do not exhibit motor and non-motor deficits compared with wild-type controls. However, SIRT3 deficiency dramatically exacerbated the degeneration of nigrostriatal dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. SIRT3 null mice exposed to MPTP also exhibited decreased superoxide dismutase 2, a specific mitochondrial antioxidant enzyme, and reduced glutathione peroxidase expression compared with wild-type controls. Taken together, these findings strongly support that SIRT3 has a possible role in MPTP-induced neurodegeneration via preserving free radical scavenging capacity in mitochondria.


Assuntos
Antioxidantes/metabolismo , Corpo Estriado/metabolismo , Intoxicação por MPTP/metabolismo , Mitocôndrias/metabolismo , Sirtuína 3/deficiência , Substância Negra/metabolismo , Animais , Corpo Estriado/patologia , Feminino , Sequestradores de Radicais Livres/metabolismo , Intoxicação por MPTP/patologia , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substância Negra/patologia
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