RESUMEN
Long-term sequelae of coronavirus disease (COVID)-19 are frequent and of major concern. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the host gut microbiota, which is linked to disease severity in patients with COVID-19. Here, we report that the gut microbiota of post-COVID subjects had a remarkable predominance of Enterobacteriaceae strains with an antibiotic-resistant phenotype compared to healthy controls. Additionally, short-chain fatty acid (SCFA) levels were reduced in feces. Fecal transplantation from post-COVID subjects to germ-free mice led to lung inflammation and worse outcomes during pulmonary infection by multidrug-resistant Klebsiella pneumoniae. transplanted mice also exhibited poor cognitive performance. Overall, we show prolonged impacts of SARS-CoV-2 infection on the gut microbiota that persist after subjects have cleared the virus. Together, these data demonstrate that the gut microbiota can directly contribute to post-COVID sequelae, suggesting that it may be a potential therapeutic target.
Asunto(s)
COVID-19 , Microbioma Gastrointestinal , Animales , Ratones , SARS-CoV-2 , Antibacterianos , Progresión de la EnfermedadRESUMEN
Annexins are well-known Ca2+ phospholipid-binding proteins, which have a wide variety of cellular functions. The role of annexin A1 (AnxA1) in the innate immune system has focused mainly on the anti-inflammatory and proresolving properties through its binding to the formyl-peptide receptor 2 (FPR2)/ALX receptor. However, studies suggesting an intracellular role of AnxA1 are emerging. In this study, we aimed to understand the role of AnxA1 for interleukin (IL)-1ß release in response to activators of the nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome. Using AnxA1 knockout mice, we observed that AnxA1 is required for IL-1ß release in vivo and in vitro. These effects were due to reduction of transcriptional levels of IL-1ß, NLRP3 and caspase-1, a step called NLRP3 priming. Moreover, we demonstrate that AnxA1 co-localize and directly bind to NLRP3, suggesting the role of AnxA1 in inflammasome activation is independent of its anti-inflammatory role via FPR2. Therefore, AnxA1 regulates NLRP3 inflammasome priming and activation in a FPR2-independent manner.
Asunto(s)
Anexina A1/metabolismo , Inflamasomas/inmunología , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Administración Intranasal , Animales , Cartílago Articular , Caspasa 1/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Gota/inducido químicamente , Gota/inmunología , Gota/patología , Humanos , Inflamasomas/metabolismo , Inyecciones Intraarticulares , Pulmón/inmunología , Pulmón/patología , Macrófagos , Masculino , Ratones , Ratones Noqueados , Cultivo Primario de Células , Unión Proteica/inmunología , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/toxicidad , Silicosis/inmunología , Silicosis/patología , Transcripción Genética/inmunología , Ácido Úrico/administración & dosificación , Ácido Úrico/toxicidadRESUMEN
The growing elderly population world widely prompts the need for studies regarding aged brain and its susceptibility to neurodegenerative diseases. It has been shown that aged brain exhibits several alterations, including neuroinflammation, which prone this organ to neurodegenerative processes. Metabotropic glutamate receptor 5 (mGlu5 receptor) has a role in neuronal cell loss and inflammation. Although the relevance of mGlu5 receptor in different diseases has been investigated, its involvement in normal brain aging remains unclear. In the present study, we used the mGlu5 receptor knockout (mGluR5-/-) mice, a model of Huntington's Disease (BACHD), and the double mutant mice (mGluR5-/-/BACHD), at the ages of 2, 6 and 12 months, to investigate whether mGlu5 receptor has a role in brain aging. We demonstrated that mGluR5-/- mice exhibit diminished number of neurons at 12 months of age in the cortex and striatum, similarly to what was observed in the case of BACHD and mGluR5-/-/BACHD mice. In addition, ablation of mGlu5 receptor increased the number of astrocytes and microglia in BACHD and wild type (WT) mice in an age-dependent manner in the cortical region, but not in the striatum. Interestingly, 12-month-old mGluR5-/- mice induced microglia activation, evidenced by increased CD68 expression and diminished number of microglia ramifications in skeleton analyses. Importantly, the presence of mutant huntingtin and the absence of mGlu5 receptor promoted decreased levels of fractalkine expression in aged mice, which could account for the decreased levels of microglia activation in these mice. Together, our data provide evidence that mGlu5 receptor plays a role in brain aging by modulating different cell types in the central nervous system (CNS).
Asunto(s)
Envejecimiento/metabolismo , Encéfalo/metabolismo , Mediadores de Inflamación/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Receptor del Glutamato Metabotropico 5/deficiencia , Envejecimiento/genética , Envejecimiento/patología , Animales , Encéfalo/patología , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Inflamación/metabolismo , Inflamación/patología , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Ratones Transgénicos , Microglía/metabolismo , Microglía/patología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Receptor del Glutamato Metabotropico 5/genéticaRESUMEN
Huntington's Disease (HD) is an autosomal-dominant neurodegenerative disorder, characterized by involuntary body movements, cognitive impairment, and psychiatric disorder. The metabotropic glutamate receptor 5 (mGluR5) plays an important role in HD and we have recently demonstrated that mGluR5-positive allosteric modulators (PAMs) can ameliorate pathology and the phenotypic signs of a mouse model of HD. In this study, we investigated the molecular mechanisms involved in mGluR5 PAMs effect on memory. Our results demonstrate that subchronic treatment with the mGluR5 PAM VU0409551 was effective in reversing the memory deficits exhibited by BACHD mice, a mouse model for HD. Moreover, VU0409551 treatment stabilized mGluR5 at the cellular plasma membrane of BACHD mice, increasing the expression of several genes important for synaptic plasticity, including c-Fos, brain-derived neurotrophic factor, Arc/Arg3.1, syntaxin 1A, and post-synaptic density-95. In addition, VU0409551 treatment also increased dendritic spine density and maturation and augmented the number of pre-synaptic sites. In conclusion, our results demonstrate that VU0409551 triggered the activation of cell signaling pathways important for synaptic plasticity, enhancing the level of dendritic spine maturation and rescuing BACHD memory impairment. OPEN PRACTICES: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.
Asunto(s)
Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/psicología , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/psicología , Plasticidad Neuronal/efectos de los fármacos , Oxazoles/farmacología , Piridinas/farmacología , Receptor del Glutamato Metabotropico 5/efectos de los fármacos , Sinapsis/efectos de los fármacos , Animales , Condicionamiento Clásico/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Enfermedad de Huntington/complicaciones , Trastornos de la Memoria/etiología , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Plasticidad Neuronal/genética , Receptor del Glutamato Metabotropico 5/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Zika virus (ZIKV) has recently caused a worldwide outbreak of infections associated with severe neurological complications, including microcephaly in infants born from infected mothers. ZIKV exhibits high neurotropism and promotes neuroinflammation and neuronal cell death. We have recently demonstrated that N-methyl-d-aspartate receptor (NMDAR) blockade by memantine prevents ZIKV-induced neuronal cell death. Here, we show that ZIKV induces apoptosis in a non-cell autonomous manner, triggering cell death of uninfected neurons by releasing cytotoxic factors. Neuronal cultures infected with ZIKV exhibit increased levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and glutamate. Moreover, infected neurons exhibit increased expression of GluN2B and augmented intracellular Ca2+ concentration. Blockade of GluN2B-containing NMDAR by ifenprodil normalizes Ca2+ levels and rescues neuronal cell death. Notably, TNF-α and IL-1ß blockade decreases ZIKV-induced Ca2+ flux through GluN2B-containing NMDARs and reduces neuronal cell death, indicating that these cytokines might contribute to NMDAR sensitization and neurotoxicity. In addition, ZIKV-infected cultures treated with ifenprodil exhibits increased activation of the neuroprotective pathway including extracellular signal-regulated kinase and cAMP response element-binding protein, which may underlie ifenprodil-mediated neuroprotection. Together, our data shed some light on the neurotoxic mechanisms triggered by ZIKV and begin to elucidate how GluN2B-containing NMDAR blockade can prevent neurotoxicity.
RESUMEN
BACKGROUND: The metabotropic glutamate receptor 5 (mGluR5) is involved in various brain functions, including memory, cognition and motor behavior. Regarding locomotor activity, we and others have demonstrated that pharmacological antagonism of mGluR5 promotes hyperkinesia in mice. Moreover, increased locomotor activity can also be observed in mice following the genetic deletion of mGluR5. However, it is still unclear which specific brain substrates contribute to mGluR5-mediated regulation of motor function. RESULTS: Thus, to better understand the role of mGluR5 in motor control and to determine which neural substrates are involved in this regulation we performed stereotactic microinfusions of the mGluR5 antagonist, MPEP, into specific brain regions and submitted mice to the open field and rotarod apparatus. Our findings indicate that mGluR5 blockage elicits distinct outcomes in terms of locomotor activity and motor coordination depending on the brain region injected with mGluR5 antagonist. MPEP injection into either the dorsal striatum or dorsal hippocampus resulted in increased locomotor activity, whereas MPEP injection into either the ventral striatum or motor cortex resulted in hypokinesia. Moreover, MPEP injected into the olfactory bulb increased the distance mice traveled in the center of the open field arena. With respect to motor coordination on the rotarod, injection of MPEP into the motor cortex and olfactory bulb elicited decreased latency to fall. CONCLUSIONS: Taken together, our data suggest that not only primarily motor neural substrates, but also limbic and sensory structures are involved in mGluR5-mediated motor behavior.