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1.
Nature ; 577(7790): 399-404, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915375

RESUMO

Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.


Assuntos
Doença de Alzheimer/imunologia , Linfócitos T CD8-Positivos/imunologia , Líquido Cefalorraquidiano/imunologia , Idoso , Sequência de Aminoácidos , Estudos de Coortes , Humanos , Memória Imunológica , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Sequência de Proteína
2.
Cell Commun Signal ; 22(1): 424, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223663

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is characterized by the abnormal proliferation of myeloid precursor cells and presents significant challenges in treatment due to its heterogeneity. Recently, the NLRP3 inflammasome has emerged as a potential contributor to AML pathogenesis, although its precise mechanisms remain poorly understood. METHODS: Public genome datasets were utilized to evaluate the expression of NLRP3 inflammasome-related genes (IL-1ß, IL-18, ASC, and NLRP3) in AML patients compared to healthy individuals. CRISPR/Cas9 technology was employed to generate NLRP3-deficient MOLM-13 AML cells, followed by comprehensive characterization using real-time PCR, western blotting, FACS analysis, and transmission electron and immunofluorescence microscopy. Proteomic analyses were conducted to identify NLRP3-dependent alterations in protein levels, with a focus on the eIF2 kinase PERK-mediated signaling pathways. Additionally, in vivo studies were performed using a leukemic mouse model to elucidate the pathogenic role of NLRP3 in AML. RESULTS: Elevated expression of NLRP3 was significantly associated with diminished overall survival in AML patients. Genetic deletion, pharmacological inhibition and silencing by RNA interference of NLRP3 led to decreased AML cell survival through the induction of apoptosis. Proteomic analyses uncovered NLRP3-dependent alterations in protein translation, characterized by enhanced eIF2α phosphorylation in NLRP3-deficient AML cells. Moreover, inhibition of PERK-mediated eIF2α phosphorylation reduced apoptosis by downregulating pro-apoptotic Bcl-2 family members. In vivo studies demonstrated reduced leukemic burden in mice engrafted with NLRP3 knockout AML cells, as evidenced by alleviated leukemic symptoms. CONCLUSION: Our findings elucidate the involvement of the NLRP3/PERK/eIF2 axis as a novel driver of AML cell survival. Targeting NLRP3-induced signaling pathways, particularly through the PERK/eIF2 axis, presents a promising therapeutic strategy for AML intervention. These insights into the role of the NLRP3 inflammasome offer potential avenues for improving the prognosis and treatment outcomes of AML patients.


Assuntos
Apoptose , Fator de Iniciação 2 em Eucariotos , Leucemia Mieloide Aguda , Proteína 3 que Contém Domínio de Pirina da Família NLR , eIF-2 Quinase , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Humanos , Apoptose/genética , Animais , Fator de Iniciação 2 em Eucariotos/metabolismo , Fator de Iniciação 2 em Eucariotos/genética , Camundongos , eIF-2 Quinase/metabolismo , eIF-2 Quinase/genética , Transdução de Sinais , Linhagem Celular Tumoral , Progressão da Doença , Inflamassomos/metabolismo
3.
Alzheimers Dement ; 14(8): 1022-1037, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29630865

RESUMO

INTRODUCTION: One characteristic of Alzheimer's disease is the formation of amyloid-ß plaques, which are typically linked to neuroinflammation and surrounded by inflammatory cells such as microglia and infiltrating immune cells. METHODS: Here, we describe nonneurogenic doublecortin (DCX) positive cells, DCX being generally used as a marker for young immature neurons, at sites of amyloid-ß plaques in various transgenic amyloid mouse models and in human brains with plaque pathology. RESULTS: The plaque-associated DCX+ cells were not of neurogenic identity, instead most of them showed coexpression with markers for microglia (ionized calcium-binding adapter molecule 1) and for phagocytosis (CD68 and TREM2). Another subpopulation of plaque-associated DCX+ cells was negative for ionized calcium-binding adapter molecule 1 but was highly positive for the pan-leukocyte marker CD45. These hematopoietic cells were identified as CD3-and CD8-positive and CD4-negative T-cells. DISCUSSION: Peculiarly, the DCX+/ionized calcium-binding adapter molecule 1+ microglia and DCX+/CD8+ T-cells were closely attached, suggesting that these two cell types are tightly interacting and that this interaction might shape plaque pathology.


Assuntos
Doença de Alzheimer/patologia , Linfócitos T CD8-Positivos , Microglia/ultraestrutura , Proteínas Associadas aos Microtúbulos/ultraestrutura , Placa Amiloide/ultraestrutura , Doença de Alzheimer/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Feminino , Humanos , Glicoproteínas de Membrana/genética , Camundongos Transgênicos , Microglia/patologia , Microscopia Eletrônica , Neuropeptídeos , Placa Amiloide/patologia , Receptores Imunológicos/genética
4.
Gut Microbes ; 16(1): 2402543, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39288239

RESUMO

Sophisticated immune evasion strategies enable Helicobacter pylori (H. pylori) to colonize the gastric mucosa of approximately half of the world's population. Persistent infection and the resulting chronic inflammation are a major cause of gastric cancer. To understand the intricate interplay between H. pylori and host immunity, spatial profiling was used to monitor immune cells in H. pylori infected gastric tissue. Dendritic cell (DC) and T cell phenotypes were further investigated in gastric organoid/immune cell co-cultures and mechanistic insights were acquired by proteomics of human DCs. Here, we show that ADP-heptose, a bacterial metabolite originally reported to act as a bona fide PAMP, reduces H. pylori-induced DC maturation and subsequent T cell responses. Mechanistically, we report that H. pylori uptake and subsequent DC activation by an ADP-heptose deficient H. pylori strain depends on TLR2. Moreover, ADP-heptose attenuates full-fledged activation of primary human DCs in the context of H. pylori infection by impairing type I IFN signaling. This study reveals that ADP-heptose mitigates host immunity during H. pylori infection.


Assuntos
Células Dendríticas , Infecções por Helicobacter , Helicobacter pylori , Receptor 2 Toll-Like , Helicobacter pylori/imunologia , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Células Dendríticas/metabolismo , Células Dendríticas/efeitos dos fármacos , Humanos , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/imunologia , Receptor 2 Toll-Like/metabolismo , Evasão da Resposta Imune , Heptoses/metabolismo , Heptoses/farmacologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Difosfato de Adenosina/metabolismo , Lipopolissacarídeos
5.
Aging (Albany NY) ; 15(3): 630-649, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36734880

RESUMO

In Alzheimer's disease (AD), platelets become dysfunctional and might contribute to amyloid beta deposition. Here, we depleted platelets in one-year-old APP Swedish PS1 dE9 (APP-PS1) transgenic mice for five days, using intraperitoneal injections of an anti-CD42b antibody, and assessed changes in cerebral amyloidosis, plaque-associated neuritic dystrophy and gliosis. In APP-PS1 female mice, platelet depletion shifted amyloid plaque size distribution towards bigger plaques and increased neuritic dystrophy in the hippocampus. In platelet-depleted females, plaque-associated Iba1+ microglia had lower amounts of fibrillar amyloid beta cargo and GFAP+ astrocytic processes showed a higher overlap with thioflavin S+ amyloid plaques. In contrast to the popular hypothesis that platelets foster plaque pathology, our data suggest that platelets might limit plaque growth and attenuate plaque-related neuritic dystrophy at advanced stages of amyloid plaque pathology in APP-PS1 female mice. Whether the changes in amyloid plaque pathology are due to a direct effect on amyloid beta deposition or are a consequence of altered glial function needs to be further elucidated.


Assuntos
Doença de Alzheimer , Camundongos , Feminino , Animais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Placa Amiloide/patologia , Camundongos Transgênicos , Modelos Animais de Doenças
6.
Front Immunol ; 14: 1290833, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38053995

RESUMO

Helicobacter pylori is a widespread Gram-negative pathogen involved in a variety of gastrointestinal diseases, including gastritis, ulceration, mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. Immune responses aimed at eradication of H. pylori often prove futile, and paradoxically play a crucial role in the degeneration of epithelial integrity and disease progression. We have previously shown that H. pylori infection of primary human monocytes increases their potential to respond to subsequent bacterial stimuli - a process that may be involved in the generation of exaggerated, yet ineffective immune responses directed against the pathogen. In this study, we show that H. pylori-induced monocyte priming is not a common feature of Gram-negative bacteria, as Acinetobacter lwoffii induces tolerance to subsequent Escherichia coli lipopolysaccharide (LPS) challenge. Although the increased reactivity of H. pylori-infected monocytes seems to be specific to H. pylori, it appears to be independent of its virulence factors Cag pathogenicity island (CagPAI), cytotoxin associated gene A (CagA), vacuolating toxin A (VacA) and γ-glutamyl transferase (γ-GT). Utilizing whole-cell proteomics complemented with biochemical signaling studies, we show that H. pylori infection of monocytes induces a unique proteomic signature compared to other pro-inflammatory priming stimuli, namely LPS and the pathobiont A. lwoffii. Contrary to these tolerance-inducing stimuli, H. pylori priming leads to accumulation of NF-кB proteins, including p65/RelA, and thus to the acquisition of a monocyte phenotype more responsive to subsequent LPS challenge. The plasticity of pro-inflammatory responses based on abundance and availability of intracellular signaling molecules may be a heretofore underappreciated form of regulating innate immune memory as well as a novel facet of the pathobiology induced by H. pylori.


Assuntos
Helicobacter pylori , NF-kappa B , Humanos , NF-kappa B/metabolismo , Proteínas de Bactérias , Imunidade Treinada , Lipopolissacarídeos/metabolismo , Proteômica
7.
Front Mol Biosci ; 10: 1196083, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37457829

RESUMO

Introduction: Alzheimer's disease (AD) and aging are associated with platelet hyperactivity. However, the mechanisms underlying abnormal platelet function in AD and aging are yet poorly understood. Methods: To explore the molecular profile of AD and aged platelets, we investigated platelet activation (i.e., CD62P expression), proteome and transcriptome in AD patients, non-demented elderly, and young individuals as controls. Results: AD, aged and young individuals showed similar levels of platelet activation based on CD62P expression. However, AD and aged individuals had a proteomic signature suggestive of increased platelet activation compared with young controls. Transcriptomic profiling suggested the dysregulation of proteolytic machinery involved in regulating platelet function, particularly the ubiquitin-proteasome system in AD and autophagy in aging. The functional implication of these transcriptomic alterations remains unclear and requires further investigation. Discussion: Our data strengthen the evidence of enhanced platelet activation in aging and provide a first glimpse of the platelet transcriptomic changes occurring in AD.

8.
Biomolecules ; 12(3)2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35327537

RESUMO

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB.


Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Sinucleinopatias , Encéfalo/metabolismo , Humanos , Leucotrienos , Doença de Parkinson/patologia , Transdução de Sinais , alfa-Sinucleína/metabolismo
9.
Science ; 374(6569): 868-874, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34648304

RESUMO

Recent studies indicate that the adaptive immune system plays a role in Lewy body dementia (LBD). However, the mechanism regulating T cell brain homing in LBD is unknown. Here, we observed T cells adjacent to Lewy bodies and dopaminergic neurons in postmortem LBD brains. Single-cell RNA sequencing of cerebrospinal fluid (CSF) identified up-regulated expression of C-X-C motif chemokine receptor 4 (CXCR4) in CD4+ T cells in LBD. CSF protein levels of the CXCR4 ligand, C-X-C motif chemokine ligand 12 (CXCL12), were associated with neuroaxonal damage in LBD. Furthermore, we observed clonal expansion and up-regulated interleukin 17A expression by CD4+ T cells stimulated with a phosphorylated α-synuclein epitope. Thus, CXCR4-CXCL12 signaling may represent a mechanistic target for inhibiting pathological interleukin-17­producing T cell trafficking in LBD.


Assuntos
Encéfalo/imunologia , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Doença por Corpos de Lewy/imunologia , Doença por Corpos de Lewy/patologia , Degeneração Neural , Animais , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Líquido Cefalorraquidiano/imunologia , Quimiocina CXCL12/metabolismo , Feminino , Humanos , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/metabolismo , Ativação Linfocitária , Masculino , Meninges/imunologia , Meninges/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Regulação para Cima , alfa-Sinucleína/análise
10.
Front Neurosci ; 14: 129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194368

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease with a complex and not fully understood pathogenesis. Besides brain-intrinsic hallmarks such as abnormal deposition of harmful proteins, i.e., amyloid beta in plaques and hyperphosphorylated Tau in neurofibrillary tangles, blood-derived elements, in particular, platelets have been discussed to be involved in AD pathogenesis. The underlying mechanisms, however, are rather unexplored. Here, we investigate a potential role of platelets in an AD transgenic animal model with severe amyloid plaque formation, the APP-PS1 transgenic mice, and analyzed the presence, spatial location and activation status of platelets within the brain. In APP-PS1 mice, a higher number of platelets were located within the brain parenchyma, i.e., outside the cerebral blood vessels compared to WT controls. Such platelets were activated according to the expression of the platelet activation marker CD62P and to morphological hallmarks such as membrane protrusions. In the brain, platelets were in close contact exclusively with astrocytes suggesting an interaction between these two cell types. In the bloodstream, although the percentage of activated platelets did not differ between transgenic and age-matched control animals, APP-PS1 blood-derived platelets showed remarkable ultrastructural peculiarities in platelet-specific organelles such as the open canalicular system (OCS). This work urges for further investigations on platelets and their yet unknown functional roles in the brain, which might go beyond AD pathogenesis and be relevant for various age-related neurodegenerative diseases.

11.
Transl Psychiatry ; 10(1): 256, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732969

RESUMO

High trait anxiety is a substantial risk factor for developing anxiety disorders and depression. While neuroinflammation has been identified to contribute to stress-induced anxiety, little is known about potential dysregulation in the neuroinflammatory system of genetically determined pathological anxiety or high trait anxiety individuals. We report microglial alterations in various brain regions in a mouse model of high trait anxiety (HAB). In particular, the dentate gyrus (DG) of the hippocampus of HABs exhibited enhanced density and average cell area of Iba1+, and density of phagocytic (CD68+/Iba1+) microglia compared to normal anxiety (NAB) controls. Minocycline was used to assess the capacity of a putative microglia 'inhibitor' in modulating hyperanxiety behavior of HABs. Chronic oral minocycline indeed reduced HAB hyperanxiety, which was associated with significant decreases in Iba1+ and CD68+Iba1+ cell densities in the DG. Addressing causality, it was demonstrated that longer (10 days), but not shorter (5 days), periods of minocycline microinfusions locally into the DG of HAB reduced Iba-1+ cell density and attenuated hyperanxiety-related behavior, indicating that neuroinflammation in the DG is at least partially involved in the maintenance of pathological anxiety. The present data reveal evidence of disturbances in the microglial system of individuals with high trait anxiety. Minocycline attenuated HAB hyperanxiety, likely by modulation of microglial activity within the DG. Thus, the present data suggest that drugs with microglia-targeted anti-inflammatory properties could be promising as novel alternative or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals genetically predisposed to hyperanxiety.


Assuntos
Ansiolíticos , Minociclina , Animais , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/tratamento farmacológico , Camundongos , Microglia , Minociclina/farmacologia
12.
Aging Dis ; 11(4): 828-850, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32765949

RESUMO

Vascular dementia (VaD) is the second leading form of memory loss after Alzheimer's disease (AD). Currently, there is no cure available. The etiology, pathophysiology and clinical manifestations of VaD are extremely heterogeneous, but the impaired cerebral blood flow (CBF) represents a common denominator of VaD. The latter might be the result of atherosclerosis, amyloid angiopathy, microbleeding and micro-strokes, together causing blood-brain barrier (BBB) dysfunction and vessel leakage, collectively originating from the consequence of hypertension, one of the main risk factors for VaD. At the histopathological level, VaD displays abnormal vascular remodeling, endothelial cell death, string vessel formation, pericyte responses, fibrosis, astrogliosis, sclerosis, microglia activation, neuroinflammation, demyelination, white matter lesions, deprivation of synapses and neuronal loss. The transforming growth factor (TGF) ß has been identified as one of the key molecular factors involved in the aforementioned various pathological aspects. Thus, targeting TGF-ß signaling in the brain might be a promising therapeutic strategy to mitigate vascular pathology and improve cognitive functions in patients with VaD. This review revisits the recent understanding of the role of TGF-ß in VaD and associated pathological hallmarks. It further explores the potential to modulate certain aspects of VaD pathology by targeting TGF-ß signaling.

13.
Neurotherapeutics ; 17(3): 1061-1074, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32072462

RESUMO

Dementia with Lewy bodies (DLB) represents a huge medical need as it accounts for up to 30% of all dementia cases, and there is no cure available. The underyling spectrum of pathology is complex and creates a challenge for targeted molecular therapies. We here tested the hypothesis that leukotrienes are involved in the pathology of DLB and that blocking leukotrienes through Montelukast, a leukotriene receptor antagonist and approved anti-asthmatic drug, might alleviate pathology and restore cognitive functions. Expression of 5-lipoxygenase, the rate-limiting enzyme for leukotriene production, was indeed elevated in brains with DLB. Treatment of cognitively deficient human alpha-synuclein overexpressing transgenic mice with Montelukast restored memory. Montelukast treatment resulted in modulation of beclin-1 expression, a marker for autophagy, and in a reduction in the human alpha-synulcein load in the transgenic mice. Reducing the protein aggregation load in neurodegenerative diseases might be a novel model of action of Montelukast. Moreover, this work presents leukotriene signaling as a potential drug target for DLB and shows that Montelukast might be a promising drug candidate for future DLB therapy development.


Assuntos
Acetatos/uso terapêutico , Ciclopropanos/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Doença por Corpos de Lewy/tratamento farmacológico , Memória/efeitos dos fármacos , Quinolinas/uso terapêutico , Receptores de Leucotrienos , Sulfetos/uso terapêutico , alfa-Sinucleína/antagonistas & inibidores , Acetatos/farmacologia , Animais , Ciclopropanos/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Antagonistas de Leucotrienos/farmacologia , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/metabolismo , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Quinolinas/farmacologia , Receptores de Leucotrienos/genética , Receptores de Leucotrienos/metabolismo , Sulfetos/farmacologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
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