RESUMO
Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.
Assuntos
Doença de Alzheimer , Camundongos , Animais , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Microglia/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Encéfalo , Homeostase , Camundongos TransgênicosRESUMO
Wound healing is a dynamic process involving the timely transition of organized phases. However, infected wounds often experience prolonged inflammation due to microbial overload. Thus, addressing the viable treatment needs across different healing stages is a critical challenge in wound management. Herein, a novel core-shell microneedle (CSMN) patch is designed for the sequential delivery of tannic acid-magnesium (TA-Mg) complexes and extracellular vesicles from Lactobacillus druckerii (LDEVs). Upon application to infected sites, CSMN@TA-Mg/LDEV releases TA-Mg first to counteract pathogenic overload and reduce reactive oxygen species (ROS), aiding the transition to proliferative phase. Subsequently, the sustained release of LDEVs enhances the activities of keratinocytes and fibroblasts, promotes vascularization, and modulates the collagen deposition. Notably, dynamic track of microbial composition demonstrates that CSMN@TA-Mg/LDEV can both inhibit the aggressive pathogen and increase the microbial diversity at wound sites. Functional analysis further highlights the potential of CSMN@TA-Mg/LDEV in facilitating wound healing and skin barrier restoration. Moreover, it is confirmed that CSMN@TA-Mg/LDEV can accelerate wound closure and improve post-recovery skin quality in the murine infected wound. Conclusively, this innovative CSMN patch offers a rapid and high-quality alternative treatment for infected wounds and emphasizes the significance of microbial homeostasis.
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Activation of innate immunity in the brain is a prominent feature of Alzheimer's disease (AD). The present study investigated the regulation of innate immunity by wild-type serum injection in a transgenic AD mouse model. We found that treatment with wild-type mouse serum significantly reduced the number of neutrophils and microglial reactivity in the brains of APP/PS1 mice. Mimicking this effect, neutrophil depletion via Ly6G neutralizing antibodies resulted in improvements in AD brain functions. Serum proteomic analysis identified vascular endothelial growth factor-A (VEGF-A) and chemokine (C-X-C motif) ligand 1 (CXCL1) as factors enriched in serum samples, which are crucial for neutrophil migration and chemotaxis, leukocyte migration, and cell chemotaxis. Exogenous VEGF-A reversed amyloid ß (Aß)-induced decreases in cyclin-dependent kinase 5 (Cdk5) and increases in CXCL1 in vitro and blocked neutrophil infiltration into the AD brain. Endothelial Cdk5 overexpression conferred an inhibitory effect on CXCL1 and neutrophil infiltration, thereby restoring memory abilities in APP/PS1 mice. Our findings uncover a previously unknown link between blood-derived VEGF signaling and neutrophil infiltration and support targeting endothelial Cdk5 signaling as a potential therapeutic strategy for AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos , Animais , Camundongos Transgênicos , Fator A de Crescimento do Endotélio Vascular , Infiltração de Neutrófilos , Proteômica , Doença de Alzheimer/terapia , Transtornos da Memória , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genéticaRESUMO
CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aß generation, yet its brain localization and functions in Alzheimer's disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G transcripts and proteins were identified in brain tissues, with the highest expression observed in neurons. Notably, AD was associated with reduced levels of CLEC4G transcripts. Bioinformatic analyses revealed interactions between CLEC4G and relevant genes such as BACE1, NPC1, PILRA, TYROBP, MGAT1, and MGAT3, all displaying a negative correlation trend. We further identified the upstream transcriptional regulators NR2F6 and XRCC4 for CLEC4G and confirmed a decrease in CLEC4G expression in APP/PS1 transgenic mice. This study highlights the role of CLEC4G in protecting against AD progression and the significance of CLEC4G for AD research and management.
Assuntos
Doença de Alzheimer , Lectinas Tipo C , Camundongos Transgênicos , Neurônios , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Neurônios/metabolismo , Camundongos , Humanos , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Encéfalo/metabolismo , Encéfalo/patologia , Regulação da Expressão Gênica , Modelos Animais de DoençasRESUMO
Developing novel lead-free perovskite materials with suitable bandgaps and superior thermal stability is crucial to boost their applications in next-generation photovoltaic technologies. High throughput screening combined with the first principles method can accurately and effectively screen out promising perovskites. Herein, we select two lead-free all-inorganic halide double perovskite materials Cs2KMI6 (M = Ga, In) from 1026 compounds with the criteria including appropriate structure factors, positive decomposition energies, and suitable direct bandgaps. We investigated the thermal and mechanical stability, geometric and electronic structures, photoelectric properties, and defect formation energies for both perovskites Cs2KMI6 (M = Ga, In). They can exhibit excellent structural formability and stability through the analysis of structure factors, elastic constants, and stable chemical potential regions. In addition, we investigate the defect effects of Cs2KMI6 (M = Ga, In) on the photovoltaic performance by evaluating the defect formation energies and transition energy levels. Based on the HSE06 functional, we calculated the energy band structures of these two compounds and demonstrate the direct bandgaps of 1.69 eV (HSE06) and 2.16 eV (HSE06) for Cs2KGaI6 and Cs2KInI6, respectively. Moreover, we predicted excellent spectroscopic limited maximum efficiencies (SLMEs) of these two perovskites with high light absorption coefficients (around 105 cm-1), for instance, the SLME of Cs2KGaI6 can reach as high as 28.39%.
RESUMO
The certified power conversion efficiency of perovskite solar cells is gradually approaching that of crystalline silicon solar cells. Accordingly, considering the advantages of improved thermal stability and environmental friendliness of lead-free all-inorganic halide double perovskites (LFAIHDPs), they have attracted considerable attention in optoelectronic applications. Herein, we review the recent progress on LFAIHDPs via heterovalent substitution of the lead element, including their geometrical and electronic structures, synthetic processes, and applications in optoelectronic devices. Many experimental and theoretical efforts have been devoted to investigating the thermal stability, defects, and optoelectronic properties of lead-free all-inorganic halide double perovskite materials, which have been presented. Lastly, we discuss the application of machine learning strategies to predict novel perovskite structures with excellent thermal stability and optoelectronic performance.
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Immune dysfunction is implicated in Alzheimer's disease (AD), whereas systemic immune modulation may be neuroprotective. Our previous results have indicated immune challenge with Bacillus Calmette-Guerin attenuates AD pathology in animal models by boosting the systemic immune system. Similarly, independent studies have shown that boosting systemic immune system, by blocking PD-1 checkpoint pathway, modifies AD. Here we hypothesized that influenza vaccine would potentiate function of moderate dose anti-PD-1 and therefore combining them might allow reducing the dose of PD-1 antibody needed to modify the disease. We found that moderate-dose PD-1 in combination with influenza vaccine effectively attenuated cognitive deficit and prevented amyloid-ß pathology build-up in APP/PS1 mice in a mechanism dependent on recruitment of peripheral monocyte-derived macrophages into the brain. Eliminating peripheral macrophages abrogated the beneficial effect. Moreover, by comparing CD11b+ compartments in the mouse parenchyma, we observed an elevated subset of Ly6C+ microglia-like cells, which are reportedly derived from peripheral monocytes. In addition, myeloid-derived suppressor cells are strongly elevated in the transgenic model used and normalized by combination treatment, indicating restoration of brain immune homeostasis. Overall, our results suggest that revitalizing brain immunity by combining IV with moderate-dose PD-1 inhibition may represent a therapeutic immunotherapy for AD.
Assuntos
Doença de Alzheimer , Vacinas contra Influenza , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Cognição , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1RESUMO
Organic molecules with thermally activated delayed fluorescence (TADF) and aggregation induced emission (AIE) properties have attracted increasing research interest due to their great potential applications in organic light emitting diodes (OLEDs), especially for those with multicolor mechanochromic luminescence (MCL) features. Theoretical research on the luminescence characteristics of organic TADF emitters based on the aggregation states is highly desired to quantify the relationship between the TADF properties and aggregation states. In this work, we study the 4,4'-(6-(9,9-dimethylacridine-10(9H)-yl)quinoline-2,3-dibenzonitrile (DMAC-CNQ) emitter with TADF and AIE properties, and calculate the photophysical properties in gas, solid and amorphous states by using the quantum mechanics and molecular mechanics (QM/MM) method. Our simulations demonstrate that the aggregation states enhance obviously the reverse intersystem crossing rates and transition dipole moments of the DMAC-CNQ emitter, and suppress the non-radiative rates from the lowest excited singlet state (S1) to ground state (S0). Specifically, the molecular stacking of DMAC-CNQ in solid phases can mainly restrict the geometric torsion of the DMAC moiety for decreasing non-radiative decay rates, and the torsion of the CNQ moiety for increasing the reverse intersystem crossing rates. As a result, the calculated fluorescence efficiencies of the DMAC-CNQ emitter in the crystal and amorphous states are 67% and 26% respectively, and in good agreement with the experimental results.
RESUMO
OBJECTIVE: Today, minimally invasive procedures have become mainstream surgical procedures. Percutaneous endoscopic transforaminal discectomy for lumbar disc herniation (LDH) requires profound knowledge of the laparoscopic lumbar anatomy. Immersive virtual reality (VR) provides three-dimensional patient-specific models to help in the process of preclinical surgical preparation. In this study, the authors investigated the efficacy of VR application in LDH for training orthopedic residents and postgraduates. METHODS: VR images of the lumbar anatomy were created with immersive VR and mAnatomy software. The study was conducted among 60 residents and postgraduates. A questionnaire was developed to assess the effect of and satisfaction with this VR-based basic and clinical fused curriculum. The teaching effect was also evaluated through a postlecture test, and the results of the prelecture surgical examination were taken as baselines. RESULTS: All participants in the VR group agreed that VR-based education is practical, attractive, and easy to operate, compared to traditional teaching, and promotes better understanding of the anatomical structures involved in LDH. Learners in the VR group achieved higher scores on an anatomical and clinical fusion test than learners in the traditional group (84.67 ± 14.56 vs 76.00 ± 16.10, p < 0.05). CONCLUSIONS: An immersive VR-based basic and clinical fused curriculum can increase residents' and postgraduates' interest and support them in mastering the structural changes and complicated symptoms of LDH. However, a simplified operational process and more realistic haptics of the VR system are necessary for further surgical preparation and application.
Assuntos
Discotomia Percutânea , Deslocamento do Disco Intervertebral , Disco Intervertebral , Realidade Virtual , Currículo , Humanos , Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/cirurgiaRESUMO
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder strongly correlated with a dysfunctional immune system. Our previous results demonstrated that inactivated influenza vaccine (IIV) facilitates hippocampal neurogenesis and blocks lipopolysaccharide (LPS)-induced cognitive impairment. However, whether IIV improves cognitive deficits in an AD mouse model remains unclear. In addition, early interventions in AD have been encouraged in recent years. Here, we investigated whether IIV immunization at the preclinical stage of AD alters the brain pathology and cognitive deficits in an APP/ PS1 mouse model. METHODS: We assessed spatial learning and memory using Morris water maze (MWM). The brain ß-amyloid (Aß) plaque burden and activated microglia were investigated by immunohistochemistry. Furthermore, flow cytometry was utilized to analyze the proportions of Treg cells in the spleen. A cytokine antibody array was performed to measure the alteration of cytokines in the brain and peripheral immune system. RESULTS: Five IIV immunizations activated microglia, reduced the Aß burden and improved the cognitive impairment. Simultaneously, the IIV-induced immune response broke peripheral immunosuppression by reducing Foxp3+ regulatory T cell (Treg) activities, whereas the restoration of Treg level in the periphery using all-trans retinoic acid (ATRA) blunted the protective effects of IIV on Aß burden and cognitive functions. Interestingly, IIV immunization might increase proinflammatory and anti-inflammatory cytokine expression in the brain of APP/PS1 mice, enhanced microglial activation, and enhanced the clustering and phagocytosis of Aß, thereby creating new homeostasis in the disordered immune microenvironment. CONCLUSIONS: Altogether, our results suggest that early multiple IIV immunizations exert a beneficial immunomodulatory effect in APP/PS1 mice by breaking Treg-mediated systemic immune tolerance, maintaining the activation of microglia and removing of Aß plaques, eventually improving cognitive deficits.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide , Amiloidose/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Vacinas contra Influenza/administração & dosagem , Presenilina-1 , Linfócitos T Reguladores/efeitos dos fármacos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Amiloidose/genética , Amiloidose/patologia , Animais , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/genética , Linfócitos T Reguladores/patologiaRESUMO
BACKGROUND: Prenatal infection is a substantial risk factor for neurodevelopmental disorders such as autism in offspring. We have previously reported that influenza vaccination (VAC) during early pregnancy contributes to neurogenesis and behavioral function in offspring. RESULTS: Here, we probe the efficacy of VAC pretreatment on autism-like behaviors in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) mouse model. We show that VAC improves abnormal fetal brain cytoarchitecture and lamination, an effect associated with promotion of intermediate progenitor cell differentiation in MIA fetal brain. These beneficial effects are sufficient to prevent social deficits in adult MIA offspring. Furthermore, whole-genome analysis suggests a strong interaction between Ikzf1 (IKAROS family zinc-finger 1) and neuronal differentiation. Intriguingly, VAC rescues excessive microglial Ikzf1 expression and attenuates microglial inflammatory responses in the MIA fetal brain. CONCLUSIONS: Our study implies that a preprocessed influenza vaccination prevents maternal bacterial infection from causing neocortical lamination impairments and autism-related behaviors in offspring.
Assuntos
Transtorno Autístico/complicações , Vacinas contra Influenza/uso terapêutico , Malformações do Desenvolvimento Cortical/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Transtornos do Comportamento Social/prevenção & controle , Animais , Animais Recém-Nascidos , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Lipopolissacarídeos/toxicidade , Masculino , Malformações do Desenvolvimento Cortical/etiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Transtornos do Comportamento Social/etiologia , Natação/fisiologia , Natação/psicologiaRESUMO
We have previously verified that neonatal hepatitis B vaccination induced hippocampal neuroinflammation and behavior impairments in mice. However, the exact mechanism of these effects remain unclear. In this study, we observed that neonatal hepatitis B vaccination induced an anti-inflammatory cytokine response lasting for 4-5â¯weeks in both the serum and the hippocampus, primarily indicated by elevated IL-4 levels. Three weeks after the vaccination schedule, however, hepatitis B vaccine (HBV)-mice showed delayed hippocampal neuroinflammation. In periphery, IL-4 is the major cytokine induced by this vaccine. Correlation analyses showed a positive relationship in the IL-4 levels between serum and hippocampus in HBV-mice. Thus, we investigated whether neonatal over-exposure to systemic IL-4 influences brain and behavior. We observed that mice injected intraperitoneally with recombinant mouse IL-4 (mIL-4) during early life had similar neuroinflammation and cognition impairment similar to those induced by neonatal hepatitis B vaccination. Next, the mechanism underlying the effects of IL-4 on brain in mice was explored using a series of experiments. In brief, these experiments showed that IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination, which involves the permeability of neonatal blood-brain barrier and the down-regulation of IL-4 receptor. This finding suggests that clinical events concerning neonatal IL-4 over-exposure, including neonatal hepatitis B vaccination and allergic asthma in human infants, may have adverse implications for brain development and cognition.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Vacinas contra Hepatite B/efeitos adversos , Hipocampo/efeitos dos fármacos , Doenças do Sistema Nervoso/induzido quimicamente , Receptores de Interleucina-4/metabolismo , Vacinação/efeitos adversos , Animais , Animais Recém-Nascidos , Barreira Hematoencefálica/efeitos dos fármacos , Citocinas/metabolismo , Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hipocampo/metabolismo , Humanos , Lactente , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso/metabolismoRESUMO
Activation of the neonatal immune system may contribute to deficits in neuronal plasticity. We have reported that neonatal vaccination with a hepatitis B vaccine (HBV) transiently impairs mood status and spatial memory involving a systemic T helper (Th) 2 bias and M1 microglial activation. Here, an EE induced microglial anti-inflammatory M2 polarization, as evidenced by selectively enhanced expression of the Arginase1 gene (Arg-1) in the hippocampus. Interestingly, knock-down of the Arg-1 gene prevented the effects of EE on restoring the dendritic spine density. Moreover, levels of the Th1-derived cytokine IFN-gamma (IFN-γ) were elevated in the choroid plexus (CP), which is the interface between the brain and the periphery. IFN-γ-blocking antibodies blunted the protective effects of an EE on spine density and LTP. Furthermore, levels of complement proteins C1q and C3 were elevated, and this elevation was associated with synapse loss induced by the HBV, whereas an EE reversed the effects of the HBV. Similarly, blockade of C1q activation clearly prevented synaptic pruning by microglia, LTP inhibition and memory deficits in hepatitis B-vaccinated mice. Together, the EE-induced increase in IFN-γ levels in the CP may disrupt systemic immunosuppression related to HBV via an IFN-γ/Arg-1/complement-dependent pathway.
Assuntos
Vacinas contra Hepatite B/efeitos adversos , Plasticidade Neuronal/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Arginase/efeitos dos fármacos , Arginase/genética , Citocinas , Meio Ambiente , Feminino , Hepatite B , Hipocampo/efeitos dos fármacos , Interferon gama/efeitos dos fármacos , Interferon gama/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/imunologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Neurogênese/imunologia , Plasticidade Neuronal/fisiologia , Células Th2/efeitos dos fármacos , Vacinação/efeitos adversosRESUMO
The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aß1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aß1-15 group, but did not reduce the ß-amyloid (Aß) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3+ regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aß1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aß1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aß1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Vacina BCG/uso terapêutico , Encéfalo/imunologia , Monócitos/imunologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/imunologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Gliose/tratamento farmacológico , Gliose/imunologia , Gliose/patologia , Humanos , Interleucina-10/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/efeitos dos fármacos , Monócitos/patologia , Fragmentos de Peptídeos/imunologia , Baço/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologiaRESUMO
BACKGROUND: The spatial learning abilities of developing mice benefit from extrinsic cues, such as an enriched environment, with concomitant enhancement in cognitive functions. Interestingly, such enhancements can be further increased through intrinsic Bacillus Calmette-Guérin (BCG) vaccination. RESULTS: Here, we first report that combined neonatal BCG vaccination and exposure to an enriched environment (Enr) induced combined neurobeneficial effects, including hippocampal long-term potentiation, and increased neurogenesis and spatial learning and memory, in mice exposed to the Enr and vaccinated with BCG relative to those in the Enr that did not receive BCG vaccination. Neonatal BCG vaccination markedly induced anti-inflammatory meningeal macrophage polarization both in regular and Enr breeding mice. The meninges are composed of the pia mater, dura mater, and choroid plexus. Alternatively, this anti-inflammatory activity of the meninges occurred simultaneously with increased expression of the neurotrophic factors BDNF/IGF-1 and the M2 microglial phenotype in the hippocampus. Our results reveal a critical role for BCG vaccination in the regulation of neurogenesis and spatial cognition through meningeal macrophage M2 polarization and neurotrophic factor expression; these effects were completely or partially prevented by minocycline or anti-IL-10 antibody treatment, respectively. CONCLUSIONS: Together, we first claim that immunological factor and environmental factor induce a combined effect on neurogenesis and cognition via a common pathway-meningeal macrophage M2 polarization. We also present a novel functional association between peripheral T lymphocytes and meningeal macrophages after evoking adaptive immune responses in the periphery whereby T lymphocytes are recruited to the meninges in response to systemic IFN-γ signaling. This leads to meningeal macrophage M2 polarization, subsequent to microglial M2 activation and neurotrophic factor expression, and eventually promotes a positive behavior.
Assuntos
Vacina BCG/administração & dosagem , Cognição/fisiologia , Meio Ambiente , Macrófagos/metabolismo , Neurogênese/fisiologia , Comportamento Espacial/fisiologia , Animais , Animais Recém-Nascidos , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Cognição/efeitos dos fármacos , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Meninges/efeitos dos fármacos , Meninges/imunologia , Meninges/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Comportamento Espacial/efeitos dos fármacosRESUMO
Neonatal Bacillus Calmette-Guérin (BCG) vaccination results in a positive effect on hippocampal neurogenesis and cognition. Serum cytokines are considered to be the chief culprit. In this study, serum from BCG-treated mice was identified as Th1 polarized serum. The serum showed an increased ratio of IFN-γ to IL-4 and decreased levels of TNF-α and IL-6. After Th1 polarized serum was injected intraperitoneally into postnatal mice, the levels of cytokines and ratio of IFN-γ to IL-4 in the serum and hippocampus of postnatal mice showed a similar alteration as those in Th1 polarized serum. This result indicated that the immune homeostatic milieu in postnatal mice was broken and the Th1 polarized systemic environment in the BCG-serum group was remodeled. The BCG-serum group displayed more BrdU+/DCX+ cells, BrdU+/NeuN+ cells, Nestin+ cells and better cognitive abilities. In neural stem cells, the Wnt7a/ß-catenin signaling pathway was activated and exposure to the Wnt7a antagonist Dickkopf-1 inhibited BCG-serum-induced Wnt7a/ß-catenin signaling, neurogenesis and cognitive function. Additionally, BCG-serum was associated with elevations in hippocampal brain-derived neurotrophic factor (BDNF) levels, and BDNF expression in the BCG-serum group was offset by Dickkopf-1 treatment. By rebalancing the Th1 polarized systemic environment in neonatal mice, it is possible that treatment with BCG-serum promotes hippocampal neurogenesis and improves cognitive functions, which are associated with Wnt7a/ß-catenin-BDNF signaling.
Assuntos
Cognição/fisiologia , Hipocampo/metabolismo , Neurogênese/fisiologia , Células Th1/fisiologia , Via de Sinalização Wnt/fisiologia , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Duplacortina , Hipocampo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Interferon gama/sangue , Interleucina-4/sangue , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Células-Tronco Neurais/fisiologia , Memória Espacial/fisiologiaRESUMO
We previously demonstrated that A(H1N1) influenza vaccine (AIV) promoted hippocampal neurogenesis and working memory in pregnant mice. However, the underlying mechanism of flu vaccination in neurogenesis and memory has remained unclear. In this study, we found that T lymphocytes were recruited from the periphery to the choroid plexus (CP) of the lateral and third (3rd) ventricles in pregnant mice vaccinated with AIV (Pre+AIV). Intracerebroventricular delivery of anti-TCR antibodies markedly decreased neurogenesis and the working memory of the Pre+AIV mice. Similarly, intravenous delivery of anti-CD4 antibodies to the periphery also down-regulated neurogenesis. Furthermore, AIV vaccination caused microglia to skew toward an M2-like phenotype (increased Arginase-1 and Ym1 mRNA levels), and elevated levels of brain-derived growth factor (BDNF) and insulin-like growth factor-1 (IGF-1) were found in the hippocampus, whereas these effects were offset by anti-TCR antibody treatment. Additionally, in the CP, the expression level of adhesion molecules and chemokines, which assist leukocytes in permeating into the brain, were also elevated after AIV vaccination of pregnant mice. Collectively, the results suggested that the infiltrative T lymphocytes in the CP contribute to the increase in hippocampal neurogenesis and working memory caused by flu vaccination, involving activation of the brain's CP, M2 microglial polarization and neurotrophic factor expression.
Assuntos
Plexo Corióideo/imunologia , Hipocampo/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/farmacologia , Neurogênese/imunologia , Prenhez/imunologia , Linfócitos T/efeitos dos fármacos , Animais , Quimiocinas/imunologia , Feminino , Vacinas contra Influenza/imunologia , Masculino , Aprendizagem em Labirinto/fisiologia , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Gravidez , Linfócitos T/imunologiaRESUMO
Response surface methodology (RSM) was used to optimize the operating conditions of an anaerobic-anoxic-oxic (A(2)/O) process by maximizing the removal efficiency of tetracycline (TC). Solid retention time (SRT), hydraulic retention time (HRT) and initial TC concentration (CTC, in) were selected as independent variables for incorporation in the Box-Behnken design. The results showed SRT and CTC, in were more significant parameters than HRT for the removal efficiency of TC. TC could be completely removed under the optimal conditions of an SRT of 15.5 days, an HRT of 9.9 h and a CTC, in of 283.3 µg L(-1). TC removal efficiencies of 99% and 96% were attained for synthetic and real wastewater, respectively, under the optimal conditions. This indicated the constructed model was validated and reliable for optimizing the A(2)/O process for TC removal.
Assuntos
Antibacterianos/química , Tetraciclina/análise , Tetraciclina/química , Águas Residuárias/química , Poluentes da Água/química , Purificação da Água/métodos , Antibacterianos/análise , Biodegradação Ambiental , Modelos Químicos , Águas Residuárias/análise , Poluentes da Água/análiseRESUMO
Prenatal influenza virus infection has been associated with an increased risk of schizophrenia. Thus, inactivated flu vaccines are widely recommended for pregnant women. In a mouse model of pregnancy, immune activation via exposure to viruses or lipopolysaccharide (LPS) impaired brain development and behavioral function in offspring. The objective of our study was to determine if flu vaccination as an immune activation could affect postnatal neurogenesis and behavior. Female C57BL/6J mice were administered A(H1N1) influenza vaccine (AIV) or seasonal influenza vaccine (SIV) early in pregnancy. We found that the offspring of vaccinated mice, especially AIV group, presented superior performance in terms of exploratory behavior and spatial ability compared with controls at postnatal day 28 (P28), but at P56, there was no significance differences among these pups. Quantification of BrdU(+)/DCX(+) and BrdU(+)/NeuN(+) cells in the dentate gyrus (DG) indicated an increase in the hippocampal neurogenesis of the pups born to both vaccinated mothers. The cytokine levels in both the serum and hippocampus changed to varying degrees. Furthermore, administration of the A(H1N1) vaccine blocked LPS-induced cognitive impairment in the progeny. Altogether, the results suggest that maternal influenza vaccination promotes neurogenesis and behavioral function, as well as protection from LPS insults in the developing offspring.
Assuntos
Comportamento Animal/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Vacinas contra Influenza/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Comportamento Animal/fisiologia , Proteína Duplacortina , Comportamento Exploratório/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Neurogênese/imunologia , GravidezRESUMO
The effectiveness of coronavirus disease 2019 (COVID-19) vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain rapidly wanes over time. Growing evidence from epidemiological studies suggests that influenza vaccination is associated with a reduction in the risk of SARS-CoV-2 infection and COVID-19 severity. However, the underlying mechanisms remain elusive. Here, we investigate the cross-reactive immune responses of influenza vaccination to SARS-CoV-2 spike protein peptides based on in vitro study. Our data indicate enhanced activation-induced-marker (AIM) expression on CD4+ T cells in influenza-vaccination (IV)-treated peripheral blood mononuclear cells (PBMCs) upon stimulation with spike-protein-peptide pools. The fractions of other immune cell subtypes, including CD8+ T cells, monocytes, NK cells, and antigen-presenting cells, were not changed between IV-treated and control PBMCs following ex vivo spike-protein-peptide stimulation. However, the classical antiviral (IFN-γ) and anti-inflammatory (IL-1RA) cytokine responses to spike-protein-peptide stimulation were still enhanced in PBMCs from both IV-immunized adult and aged mice. Decreased expression of proinflammatory IL-1ß, IL-12p40, and TNF-α is associated with inhibited levels of histone acetylation in PBMCs from IV-treated mice. Remarkably, prior immunity to SARS-CoV-2 does not result in modification of histone acetylation or hemagglutinin-protein-induced cytokine responses. This response is antibody-independent but can be mediated by manipulating the histone acetylation of PBMCs. These data experimentally support that influenza vaccination could induce modification of histone acetylation in immune cells and reveal the existence of potential cross-reactive immunity to SARS-CoV-2 antigens, which may provide insights for the adjuvant of influenza vaccine to limit COVID-19-related inflammatory responses.