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1.
Sci Rep ; 14(1): 13618, 2024 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871799

RESUMO

The mechanism by which subarachnoid hemorrhage (SAH) leads to chronic neurologic deficits is unclear. One possibility is that blood activates microglia to drive inflammation that leads to synaptic loss and impaired brain function. Using the endovascular perforation model of SAH in rats, we investigated short-term effects on microglia together with long-term effects on EEG and neurologic function for up to 3 months. Within the first week, microglia were increased both at the site of injury and diffusely across the cortex (2.5-fold increase in SAH compared to controls, p = 0.012). Concomitantly, EEGs from SAH animals showed focal increases in slow wave activity and diffuse reduction in fast activity. When expressed as a fast-slow spectral ratio, there were significant interactions between group and time (p < 0.001) with less ipsilateral recovery over time. EEG changes were most pronounced during the first week and correlated with neurobehavioral impairment. In vitro, the blood product hemin was sufficient to increase microglia phagocytosis nearly six-fold (p = 0.032). Immunomodulatory treatment with fingolimod after SAH reduced microglia, improved neurological function, and increased survival. These findings, which parallel many of the EEG changes seen in patients, suggest that targeting neuroinflammation could reduce long-term neurologic dysfunction following SAH.


Assuntos
Modelos Animais de Doenças , Eletroencefalografia , Microglia , Hemorragia Subaracnóidea , Hemorragia Subaracnóidea/fisiopatologia , Hemorragia Subaracnóidea/complicações , Animais , Microglia/patologia , Microglia/metabolismo , Ratos , Masculino , Fagocitose , Ratos Sprague-Dawley
2.
Nat Commun ; 15(1): 5031, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866759

RESUMO

Alzheimer's disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization. Notably, less distinct connectivity patterns ("gradient contraction") are associated with cognitive decline in regions with greater tau, suggesting an interaction between reduced network differentiation and tau on cognition. Furthermore, by modeling tau in subject-specific gradient space, we demonstrate that tau accumulation in the frontoparietal and temporo-occipital cortices is associated with greater baseline tau within their functionally and structurally connected hubs, respectively. Our work unveils a role for both functional and structural brain organization in pathology accumulation in AD, and supports subject-specific gradient space as a promising tool to map disease progression.


Assuntos
Doença de Alzheimer , Encéfalo , Imageamento por Ressonância Magnética , Proteínas tau , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Proteínas tau/metabolismo , Masculino , Feminino , Idoso , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Microglia/metabolismo , Microglia/patologia , Idoso de 80 Anos ou mais , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/diagnóstico por imagem , Pessoa de Meia-Idade , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Rede Nervosa/diagnóstico por imagem , Mapeamento Encefálico/métodos
3.
Nat Commun ; 15(1): 5013, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866782

RESUMO

Multiple sclerosis (MS) is characterized by heterogeneity in disease course and prediction of long-term outcome remains a major challenge. Here, we investigate five myeloid markers - CHIT1, CHI3L1, sTREM2, GPNMB and CCL18 - in the cerebrospinal fluid (CSF) at diagnostic lumbar puncture in a longitudinal cohort of 192 MS patients. Through mixed-effects and machine learning models, we show that CHIT1 is a robust predictor for faster disability progression. Integrative analysis of 11 CSF and 26 central nervous system (CNS) parenchyma single-cell/nucleus RNA sequencing samples reveals CHIT1 to be predominantly expressed by microglia located in active MS lesions and enriched for lipid metabolism pathways. Furthermore, we find CHIT1 expression to accompany the transition from a homeostatic towards a more activated, MS-associated cell state in microglia. Neuropathological evaluation in post-mortem tissue from 12 MS patients confirms CHIT1 production by lipid-laden phagocytes in actively demyelinating lesions, already in early disease stages. Altogether, we provide a rationale for CHIT1 as an early biomarker for faster disability progression in MS.


Assuntos
Biomarcadores , Progressão da Doença , Microglia , Esclerose Múltipla , Humanos , Microglia/metabolismo , Microglia/patologia , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/patologia , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Hexosaminidases/metabolismo , Hexosaminidases/genética , Hexosaminidases/líquido cefalorraquidiano , Estudos Longitudinais , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/metabolismo , Proteína 1 Semelhante à Quitinase-3/genética
4.
Neurobiol Dis ; 198: 106554, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38844243

RESUMO

Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss. Immunohistochemistry was conducted on MTG paraffin-embedded tissue microarrays (TMAs) comprising 29 HD and 35 neurologically normal cases to compare the immunoreactivity patterns of key astrocytic proteins (glial fibrillary acidic protein, GFAP; inwardly rectifying potassium channel 4.1, Kir4.1; glutamate transporter-1, GLT-1; aquaporin-4, AQP4), key microglial proteins (ionised calcium-binding adapter molecule-1, IBA-1; human leukocyte antigen (HLA)-DR; transmembrane protein 119, TMEM119; purinergic receptor P2RY12, P2RY12), and indicators of proliferation (Ki-67; proliferative cell nuclear antigen, PCNA). Our findings demonstrate an upregulation of GFAP+ protein expression attributed to the presence of more GFAP+ expressing cells in HD, which correlated with greater cortical mutant huntingtin (mHTT) deposition. In contrast, Kir4.1, GLT-1, and AQP4 immunoreactivity levels were unchanged in HD. We also demonstrate an increased number of IBA-1+ and TMEM119+ microglia with somal enlargement. IBA-1+, TMEM119+, and P2RY12+ reactive microglia immunophenotypes were also identified in HD, evidenced by the presence of rod-shaped, hypertrophic, and dystrophic microglia. In HD cases, IBA-1+ cells contained either Ki-67 or PCNA, whereas GFAP+ astrocytes were devoid of proliferative nuclei. These findings suggest cortical microgliosis may be driven by proliferation in HD, supporting the hypothesis of microglial proliferation as a feature of HD pathophysiology. In contrast, astrocytes in HD demonstrate an altered GFAP expression profile that is associated with the degree of mHTT deposition.


Assuntos
Astrócitos , Proliferação de Células , Doença de Huntington , Microglia , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Microglia/metabolismo , Microglia/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Proliferação de Células/fisiologia , Adulto , Idoso , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Gliose/metabolismo , Gliose/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Membrana , Proteínas dos Microfilamentos
7.
Sci Rep ; 14(1): 14205, 2024 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902507

RESUMO

Acetaminophen (APAP) is a leading cause of acute liver failure. The effect of APAP metabolite's effects in the periphery are well characterized; however, associated consequences in the brain remain poorly understood. Animal studies on this subject are few and reveal that frequent APAP intake can trigger cerebral abnormalities that vary depending on the subject's age. Alarmingly, experimental efforts have yet to examine associated consequences in elderly hosts, who correspond to the highest risk of medication overload, impaired drug clearance, and cognitive deficits. Here, we interrogated the cerebral and peripheral pathology of elderly mice submitted to monthly episodes of APAP intoxication since a young adult age. We found that weeks after the final episode of recurrent APAP exposure, mice exhibited worsened non-spatial memory deficit whereas spatial memory performance was unaltered. Interestingly, one month after the period of APAP intoxication, these mice showed increased glial burden without associated drivers, namely, blood-brain barrier disruption, cholesterol accumulation, and elevation of inflammatory molecules in the brain and/or periphery. Our experimental study reveals how recurrent APAP exposure affects the cognitive performance and cellular events in elderly brains. These data suggest that APAP-containing pharmacological interventions may foreshadow the elevated risk of neuropsychiatric disorders that afflict elderly populations.


Assuntos
Acetaminofen , Astrócitos , Disfunção Cognitiva , Microglia , Animais , Acetaminofen/toxicidade , Acetaminofen/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/patologia , Disfunção Cognitiva/metabolismo , Camundongos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Microglia/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Masculino , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Camundongos Endogâmicos C57BL , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Envelhecimento , Modelos Animais de Doenças , Memória Espacial/efeitos dos fármacos
8.
Nat Commun ; 15(1): 5199, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890305

RESUMO

Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.


Assuntos
Depressão , Estresse do Retículo Endoplasmático , Retículo Endoplasmático , Camundongos Endogâmicos C57BL , Microglia , Mitocôndrias , Proteína 3 que Contém Domínio de Pirina da Família NLR , Derrota Social , Estresse Psicológico , Canal de Ânion 1 Dependente de Voltagem , Animais , Mitocôndrias/metabolismo , Depressão/metabolismo , Microglia/metabolismo , Microglia/patologia , Camundongos , Masculino , Retículo Endoplasmático/metabolismo , Estresse Psicológico/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Canal de Ânion 1 Dependente de Voltagem/genética , Hipocampo/metabolismo , Hipocampo/patologia , Trifosfato de Adenosina/metabolismo , Inflamassomos/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Cálcio/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Comportamento Animal , Membranas Associadas à Mitocôndria , Proteínas de Choque Térmico HSP70
9.
Gut Microbes ; 16(1): 2363014, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38904096

RESUMO

Gut bacteria regulate brain pathology of Alzheimer's disease (AD) patients and animal models; however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene were treated with antibiotics-supplemented or normal drinking water for 2 months. The antibiotic treatment eradicated almost all intestinal bacteria, which led to a reduction in Il-17a-expressing CD4-positive T lymphocytes in the spleen and gut, and to a decrease in bacterial DNA in brain tissue. Depletion of gut bacteria inhibited inflammatory activation in both brain tissue and microglia, lowered cerebral Aß levels, and promoted transcription of Arc gene in the brain of APP-transgenic mice, all of which effects were abolished by deficiency of Il-17a. As possible mechanisms regulating Aß pathology, depletion of gut bacteria inhibited ß-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also reversed by the absence of Il-17a. Interestingly, a crossbreeding experiment between APP-transgenic mice and Il-17a knockout mice further showed that deficiency of Il-17a had already increased Abcb1 and Lrp1 expression at the blood-brain barrier. Thus, depletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a-involved signaling pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology and highlights the therapeutic potential of Il-17a inhibition or specific depletion of gut bacteria that stimulate the development of Il-17a-expressing T cells.


Assuntos
Doença de Alzheimer , Encéfalo , Modelos Animais de Doenças , Microbioma Gastrointestinal , Interleucina-17 , Camundongos Transgênicos , Animais , Doença de Alzheimer/microbiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Interleucina-17/metabolismo , Interleucina-17/genética , Camundongos , Encéfalo/patologia , Encéfalo/metabolismo , Feminino , Camundongos Knockout , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/metabolismo , Antibacterianos/farmacologia , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Microglia/microbiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/microbiologia , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade
10.
J Neuroinflammation ; 21(1): 148, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840180

RESUMO

BACKGROUND: White matter injury (WMI) represents a significant etiological factor contributing to neurological impairment subsequent to Traumatic Brain Injury (TBI). CD36 receptors are recognized as pivotal participants in the pathogenesis of neurological disorders, including stroke and spinal cord injury. Furthermore, dynamic fluctuations in the phenotypic polarization of microglial cells have been intimately associated with the regenerative processes within the injured tissue following TBI. Nevertheless, there is a paucity of research addressing the impact of CD36 receptors on WMI and microglial polarization. This investigation aims to elucidate the functional role and mechanistic underpinnings of CD36 in modulating microglial polarization and WMI following TBI. METHODS: TBI models were induced in murine subjects via controlled cortical impact (CCI). The spatiotemporal patterns of CD36 expression were examined through quantitative polymerase chain reaction (qPCR), Western blot analysis, and immunofluorescence staining. The extent of white matter injury was assessed via transmission electron microscopy, Luxol Fast Blue (LFB) staining, and immunofluorescence staining. Transcriptome sequencing was employed to dissect the molecular mechanisms underlying CD36 down-regulation and its influence on white matter damage. Microglial polarization status was ascertained using qPCR, Western blot analysis, and immunofluorescence staining. In vitro, a Transwell co-culture system was employed to investigate the impact of CD36-dependent microglial polarization on oligodendrocytes subjected to oxygen-glucose deprivation (OGD). RESULTS: Western blot and qPCR analyses revealed that CD36 expression reached its zenith at 7 days post-TBI and remained sustained at this level thereafter. Immunofluorescence staining exhibited robust CD36 expression in astrocytes and microglia following TBI. Genetic deletion of CD36 ameliorated TBI-induced white matter injury, as evidenced by a reduced SMI-32/MBP ratio and G-ratio. Transcriptome sequencing unveiled differentially expressed genes enriched in processes linked to microglial activation, regulation of neuroinflammation, and the TNF signaling pathway. Additionally, bioinformatics analysis pinpointed the Traf5-p38 axis as a critical signaling pathway. In vivo and in vitro experiments indicated that inhibition of the CD36-Traf5-MAPK axis curtailed microglial polarization toward the pro-inflammatory phenotype. In a Transwell co-culture system, BV2 cells treated with LPS + IFN-γ exacerbated the damage of post-OGD oligodendrocytes, which could be rectified through CD36 knockdown in BV2 cells. CONCLUSIONS: This study illuminates that the suppression of CD36 mitigates WMI by constraining microglial polarization towards the pro-inflammatory phenotype through the down-regulation of the Traf5-MAPK signaling pathway. Our findings present a potential therapeutic strategy for averting neuroinflammatory responses and ensuing WMI damage resulting from TBI.


Assuntos
Antígenos CD36 , Camundongos Endogâmicos C57BL , Microglia , Animais , Microglia/metabolismo , Microglia/patologia , Camundongos , Antígenos CD36/metabolismo , Antígenos CD36/genética , Camundongos Knockout , Substância Branca/patologia , Substância Branca/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Polaridade Celular/fisiologia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Transdução de Sinais/fisiologia
11.
eNeuro ; 11(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38834299

RESUMO

Viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), use respiratory epithelial cells as an entry point for infection. Within the nasal cavity, the olfactory epithelium (OE) is particularly sensitive to infections which may lead to olfactory dysfunction. In patients suffering from coronavirus disease 2019, deficits in olfaction have been characterized as a distinctive symptom. Here, we used the K18hACE2 mice to study the spread of SARS-CoV-2 infection and inflammation in the olfactory system (OS) after 7 d of infection. In the OE, we found that SARS-CoV-2 selectively targeted the supporting/sustentacular cells (SCs) and macrophages from the lamina propria. In the brain, SARS-CoV-2 infected some microglial cells in the olfactory bulb (OB), and there was a widespread infection of projection neurons in the OB, piriform cortex (PC), and tubular striatum (TuS). Inflammation, indicated by both elevated numbers and morphologically activated IBA1+ cells (monocyte/macrophage lineages), was preferentially increased in the OE septum, while it was homogeneously distributed throughout the layers of the OB, PC, and TuS. Myelinated OS axonal tracts, the lateral olfactory tract, and the anterior commissure, exhibited decreased levels of 2',3'-cyclic-nucleotide 3'-phosphodiesterase, indicative of myelin defects. Collectively, our work supports the hypothesis that SARS-CoV-2 infected SC and macrophages in the OE and, centrally, microglia and subpopulations of OS neurons. The observed inflammation throughout the OS areas and central myelin defects may account for the long-lasting olfactory deficit.


Assuntos
COVID-19 , Bainha de Mielina , Bulbo Olfatório , Mucosa Olfatória , SARS-CoV-2 , Animais , COVID-19/patologia , COVID-19/complicações , Camundongos , Mucosa Olfatória/patologia , Mucosa Olfatória/virologia , Bulbo Olfatório/patologia , Bulbo Olfatório/virologia , Bainha de Mielina/patologia , Bainha de Mielina/metabolismo , Microglia/patologia , Microglia/metabolismo , Microglia/virologia , Camundongos Transgênicos , Enzima de Conversão de Angiotensina 2/metabolismo , Transtornos do Olfato/patologia , Transtornos do Olfato/virologia , Modelos Animais de Doenças , Masculino , Inflamação/patologia , Inflamação/virologia , Macrófagos/patologia , Feminino
12.
Sci Rep ; 14(1): 13749, 2024 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877012

RESUMO

Prion diseases are fatal, infectious, neurodegenerative disorders resulting from accumulation of misfolded cellular prion protein in the brain. Early pathological changes during CNS prion disease also include reactive astrocyte activation with increased CD44 expression, microgliosis, as well as loss of dendritic spines and synapses. CD44 is a multifunctional cell surface adhesion and signalling molecule which is considered to play roles in astrocyte morphology and the maintenance of dendritic spine integrity and synaptic plasticity. However, the role of CD44 in prion disease was unknown. Here we used mice deficient in CD44 to determine the role of CD44 during prion disease. We show that CD44-deficient mice displayed no difference in their response to CNS prion infection when compared to wild type mice. Furthermore, the reactive astrocyte activation and microgliosis that accompanies CNS prion infection was unimpaired in the absence of CD44. Together, our data show that although CD44 expression is upregulated in reactive astrocytes during CNS prion disease, it is dispensable for astrocyte and microglial activation and the development of prion neuropathogenesis.


Assuntos
Astrócitos , Receptores de Hialuronatos , Doenças Priônicas , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/genética , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Doenças Priônicas/genética , Camundongos , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Camundongos Endogâmicos C57BL
13.
Sci Transl Med ; 16(751): eadj9672, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38865481

RESUMO

Cancer treatment with anti-PD-1 immunotherapy can cause central nervous system immune-related adverse events (CNS-irAEs). The role of microglia in anti-PD-1 immunotherapy-induced CNS-irAEs is unclear. We found that anti-PD-1 treatment of mice caused morphological signs of activation and major histocompatibility complex (MHC) class II up-regulation on microglia. Functionally, anti-PD-1 treatment induced neurocognitive deficits in mice, independent of T cells, B cells, and natural killer cells. Instead, we found that microglia mediated these CNS-irAEs. Single-cell RNA sequencing revealed major transcriptional changes in microglia upon anti-PD-1 treatment. The anti-PD-1 effects were mediated by anti-PD-1 antibodies interacting directly with microglia and were not secondary to peripheral T cell activation. Using a proteomics approach, we identified spleen tyrosine kinase (Syk) as a potential target in activated microglia upon anti-PD-1 treatment. Syk inhibition reduced microglia activation and improved neurocognitive function without impairing anti-melanoma effects. Moreover, we analyzed CNS tissue from a patient cohort that had received anti-PD-1 treatment. Imaging mass cytometry revealed that anti-PD-1 treatment of patients was associated with increased surface marker expression indicative of microglia activation. In summary, we identified a disease-promoting role for microglia in CNS-irAEs driven by Syk and provide an inhibitor-based approach to interfere with this complication after anti-PD-1 immunotherapy.


Assuntos
Sistema Nervoso Central , Imunoterapia , Microglia , Receptor de Morte Celular Programada 1 , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Imunoterapia/efeitos adversos , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Humanos , Sistema Nervoso Central/patologia , Sistema Nervoso Central/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Quinase Syk/metabolismo , Camundongos
14.
Sci Transl Med ; 16(751): eadi3259, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38865485

RESUMO

Robust structural remodeling and synaptic plasticity occurs within spinal autonomic circuitry after severe high-level spinal cord injury (SCI). As a result, normally innocuous visceral or somatic stimuli elicit uncontrolled activation of spinal sympathetic reflexes that contribute to systemic disease and organ-specific pathology. How hyperexcitable sympathetic circuitry forms is unknown, but local cues from neighboring glia likely help mold these maladaptive neuronal networks. Here, we used a mouse model of SCI to show that microglia surrounded active glutamatergic interneurons and subsequently coordinated multi-segmental excitatory synaptogenesis and expansion of sympathetic networks that control immune, neuroendocrine, and cardiovascular functions. Depleting microglia during critical periods of circuit remodeling after SCI prevented maladaptive synaptic and structural plasticity in autonomic networks, decreased the frequency and severity of autonomic dysreflexia, and prevented SCI-induced immunosuppression. Forced turnover of microglia in microglia-depleted mice restored structural and functional indices of pathological dysautonomia, providing further evidence that microglia are key effectors of autonomic plasticity. Additional data show that microglia-dependent autonomic plasticity required expression of triggering receptor expressed on myeloid cells 2 (Trem2) and α2δ-1-dependent synaptogenesis. These data suggest that microglia are primary effectors of autonomic neuroplasticity and dysautonomia after SCI in mice. Manipulating microglia may be a strategy to limit autonomic complications after SCI or other forms of neurologic disease.


Assuntos
Microglia , Plasticidade Neuronal , Traumatismos da Medula Espinal , Animais , Microglia/patologia , Microglia/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/patologia , Camundongos , Receptores Imunológicos/metabolismo , Glicoproteínas de Membrana/metabolismo , Sistema Nervoso Autônomo/fisiopatologia , Camundongos Endogâmicos C57BL , Sinapses/metabolismo , Interneurônios/metabolismo
15.
Neuropathol Appl Neurobiol ; 50(3): e12992, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831600

RESUMO

PURPOSE: Radiation-induced brain injury, one of the side effects of cranial radiotherapy in tumour patients, usually results in durable and serious cognitive disorders. Microglia are important innate immune-effector cells in the central nervous system. However, the interaction between microglia and neurons in radiation-induced brain injury remains uncharacterised. METHODS AND MATERIALS: We established a microglia-neuron indirect co-culture model to assess the interaction between them. Microglia exposed to radiation were examined for pyroptosis using lactate dehydrogenase (LDH) release, Annexin V/PI staining, SYTOX staining and western blot. The role of nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) was investigated in microglia exposed to radiation and in mouse radiation brain injury model through siRNA or inhibitor. Mini-mental state examination and cytokines in blood were performed in 23 patients who had experienced cranial irradiation. RESULTS: Microglia exerted neurotoxic features after radiation in the co-culture model. NLRP3 was up-regulated in microglia exposed to radiation, and then caspase-1 was activated. Thus, the gasdermin D protein was cleaved, and it triggered pyroptosis in microglia, which released inflammatory cytokines. Meanwhile, treatment with siRNA NLRP3 in vitro and NLRP3 inhibitor in vivo attenuated the damaged neuron cell and cognitive impairment, respectively. What is more, we found that the patients after radiation with higher IL-6 were observed to have a decreased MMSE score. CONCLUSIONS: These findings indicate that radiation-induced pyroptosis in microglia may promote radiation-induced brain injury via the secretion of neurotoxic cytokines. NLRP3 was evaluated as an important mediator in radiation-induced pyroptosis and a promising therapeutic target for radiation-induced brain injury.


Assuntos
Lesões Encefálicas , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Piroptose/efeitos da radiação , Piroptose/fisiologia , Microglia/metabolismo , Microglia/efeitos da radiação , Microglia/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Camundongos , Humanos , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/etiologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Neurônios/efeitos da radiação , Técnicas de Cocultura , Lesões por Radiação/patologia , Lesões por Radiação/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
16.
Cell Signal ; 120: 111210, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38705503

RESUMO

Microglia mediated neuroinflammation is one of the major contributors to brain damage in cerebral ischemia reperfusion injury (CI/RI). Recently, RNA modification was found to contribute to the regulation of microglia polarization and the subsequent development of cerebral I/R neuroinflammation. Herein, we investigated the effect and mechanism of m5C RNA modification in the microglia induced CI/RI neuroinflammation. We found that the m5C RNA modification levels decreased in the primary microglia isolated from a mouse model of intraluminal middle cerebral artery occlusion/reperfusion (MCAO/R) and the BV2 microglial cells subjected to oxygen-glucose deprivation and reoxygenation (OGD/R), and this change was accompanied by an increase in the M1/M2 polarization ratio. Furthermore, the expression of m5C demethylase TET1 in microglia increased, which promoted M1 polarization but impeded M2 polarization. Mechanistically, the higher TET1 expression decreased the m5C modification level of RelB and enhanced its mRNA stability, which subsequently increased the M1/M2 polarization ratio. In conclusion, this study provides insight into the role of m5C RNA modification in the pathogenesis of cerebral I/R neuroinflammation and may deepen our understanding on clinical therapy targeting the TET1-RelB axis.


Assuntos
Microglia , Doenças Neuroinflamatórias , Proteínas Proto-Oncogênicas , Traumatismo por Reperfusão , Fator de Transcrição RelB , Animais , Microglia/metabolismo , Microglia/patologia , Fator de Transcrição RelB/metabolismo , Fator de Transcrição RelB/genética , Camundongos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Proteínas Proto-Oncogênicas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Polaridade Celular , Oxigenases de Função Mista/metabolismo , Oxigenases de Função Mista/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/complicações , Modelos Animais de Doenças , Proteínas de Ligação a DNA
17.
Cells ; 13(10)2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38786054

RESUMO

Prion diseases are rare and neurodegenerative diseases that are characterized by the misfolding and infectious spread of the prion protein in the brain, causing progressive and irreversible neuronal loss and associated clinical and behavioral manifestations in humans and animals, ultimately leading to death. The brain has a complex network of neurons and glial cells whose crosstalk is critical for function and homeostasis. Although it is established that prion infection of neurons is necessary for clinical disease to occur, debate remains in the field as to the role played by glial cells, namely astrocytes and microglia, and whether these cells are beneficial to the host or further accelerate disease. Here, we review the current literature assessing the complex morphologies of astrocytes and microglia, and the crosstalk between these two cell types, in the prion-infected brain.


Assuntos
Neuroglia , Doenças Priônicas , Humanos , Doenças Priônicas/patologia , Doenças Priônicas/metabolismo , Animais , Neuroglia/patologia , Neuroglia/metabolismo , Astrócitos/patologia , Astrócitos/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Neurobiologia , Microglia/patologia , Microglia/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Neuropatologia , Príons/metabolismo
18.
Exp Cell Res ; 439(1): 114088, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38744409

RESUMO

Neuroinflammation mediated by microglia plays an important role in the etiology of Parkinson's disease (PD). Rho family GTPase 3 (RND3) exerts anti-inflammatory effects and may act as a potential new inducer of neuroprotective phenotypes in microglia. However, whether RND3 can be used to regulate microglia activation or reduce neuroinflammation in PD remains elusive. The study investigated the microglia modulating effects and potential anti-inflammatory effects of RND3 in vivo and in vitro, using animal models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and cell models of BV-2 cells stimulated by LPS plus IFN-γ with or without RND3-overexpression. The results showed that RND3 was highly expressed in the MPTP-induced PD mouse model and BV-2 cells treated with LPS and IFN-γ. In vivo experiments confirmed that RND3 overexpression could modulate microglia phenotype and ameliorate MPTP-induced neuroinflammation through inhibiting activation of the NLRP3 inflammasome in substantia nigra pars compacta (SNpc). In vitro study showed that RND3 overexpression could attenuate the production of pro-inflammatory factors in BV2 cells stimulated by LPS and IFN-γ. Mechanistically, RND3 reduced the activation of the NLRP3 inflammasome upon LPS and IFN-γ stimulation. Taken together, these findings suggest that RND3 modulates microglial polarization and alleviates neuroinflammation in Parkinson's disease by suppressing NLRP3 inflammasome activation.


Assuntos
Inflamassomos , Camundongos Endogâmicos C57BL , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Doença de Parkinson , Proteínas rho de Ligação ao GTP , Animais , Microglia/metabolismo , Microglia/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Camundongos , Inflamassomos/metabolismo , Masculino , Proteínas rho de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/genética , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Lipopolissacarídeos/farmacologia , Modelos Animais de Doenças , Polaridade Celular , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética , Interferon gama/metabolismo
19.
Neuroscience ; 549: 65-75, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38750924

RESUMO

Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson's disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.


Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Sintomas Prodrômicos , Substância Negra , Animais , Masculino , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Doenças Neuroinflamatórias/patologia , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ansiedade/etiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia
20.
Eur J Pharmacol ; 975: 176659, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38762158

RESUMO

Obstructive sleep apnea syndrome (OSAS), characterized by repeated narrow or collapse of the upper airway during sleep, resulting in periodic reductions or cessations in ventilation, consequent hypoxia, hypercapnia, increased sympathetic activity and sleep fragmentation, places a serious burden on society and health care. Intermittent hypoxia (IH), which cause central nervous system (CNS) inflammation, and ultimately lead to neuropathy, is thought to be a crucial contributor to cognitive impairment in OSAS. Wnt signaling pathway exerts an important role in the regulation of CNS disorders. Particularly, it may be involved in the regulation of neuroinflammation and cognitive dysfunction. However, its underlying mechanism remains poorly understood. Accumulating evidence demonstrated that Wnt signaling pathway may inhibited in a variety of neurological disorders. Recently studies revealed that SUMOylation was participated in the regulation of neuroinflammation. Members of Wnt/ß-catenin pathway may be targets of SUMOylation. In vitro and in vivo molecular biology experiments explored the regulatory mechanism of SUMOylation on Wnt/ß-catenin in IH-induced neuroinflammation and neuronal injury, which demonstrated that IH induced the SUMOylation of ß-catenin, microglia mediated inflammation and neuronal damage. Moreover, SENP1 regulated the de-SUMOylation of ß-catenin, triggered Wnt/ß-catenin pathway, and alleviated neuroinflammation and neuronal injury, thus improving IH-related mice cognitive dysfunction.


Assuntos
Disfunção Cognitiva , Cisteína Endopeptidases , Hipóxia , Microglia , Sumoilação , Via de Sinalização Wnt , Animais , Microglia/metabolismo , Microglia/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/etiologia , Camundongos , Cisteína Endopeptidases/metabolismo , Hipóxia/complicações , Hipóxia/metabolismo , Masculino , beta Catenina/metabolismo , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/fisiopatologia , Humanos , Modelos Animais de Doenças
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