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1.
Front Aging Neurosci ; 13: 789834, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867307

RESUMO

The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer's disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

2.
J Neuroinflammation ; 18(1): 286, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34893068

RESUMO

BACKGROUND: TREM2 is a microglial receptor genetically linked to the risk for Alzheimer's disease (AD). The cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2) have emerged as a valuable biomarker for the disease progression in AD and higher CSF levels of sTREM2 are linked to slower cognitive decline. Increasing sTREM2 in mouse models of amyloidosis reduces amyloid-related pathology through modulating microglial functions, suggesting a beneficial role of sTREM2 in microglia biology and AD pathology. METHODS: In the current study, we performed serial C- and N-terminal truncations of sTREM2 protein to define the minimal sequence requirement for sTREM2 function. We initially assessed the impacts of sTREM2 mutants on microglial functions by measuring cell viability and inflammatory responses. The binding of the sTREM2 mutants to oligomeric Aß was determined by solid-phase protein binding assay and dot blot assay. We further evaluated the impacts of sTREM2 mutants on amyloid-related pathology by direct stereotaxic injection of sTREM2 proteins into the brain of 5xFAD mice. RESULTS: We found that both sTREM2 fragments 41-81 and 51-81 enhance cell viability and inflammatory responses in primary microglia. However, the fragment 51-81 exhibited impaired affinity to oligomeric Aß. When administrated to the 5xFAD mice brain, the sTREM2 fragment 41-81, but not 51-81, increased the number of plaque-associated microglia and reduced the plaque deposition. Interestingly, the fragment 41-81 was more efficient than the physiological form of sTREM2 in ameliorating Aß-related pathology. CONCLUSIONS: Our results indicate that the interaction of sTREM2 truncated variants with Aß is essential for enhancing microglial recruitment to the vicinity of an amyloid plaque and reducing the plaque load. Importantly, we identified a 41-amino acid sequence of sTREM2 that is sufficient for modulating microglial functions and more potent than the full-length sTREM2 in reducing the plaque load and the plaque-associated neurotoxicity. Taken together, our data provide more insights into the mechanisms underlying sTREM2 function and the minimal active sTREM2 sequence represents a promising candidate for AD therapy.

3.
J Hematol Oncol ; 14(1): 196, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794493

RESUMO

Myeloid-derived suppressor cells (MDSCs) are derived from bone marrow progenitor cells commonly, which is a heterogeneous cell group composed of immature granulocytes, dendritic cells, macrophages and early undifferentiated bone marrow precursor cells. Its differentiation and immunosuppressive function are regulated by complex network signals, but the specific regulation mechanisms are not yet fully understood. In this study, we found that in mouse of Lewis lung cancer xenograft, long non-coding RNA Snhg6 (lncRNA Snhg6) was highly expressed in tumor-derived MDSCs compared with spleen-derived MDSCs. LncRNA Snhg6 facilitated the differentiation of CD11b+ Ly6G- Ly6Chigh monocytic MDSCs (Mo-MDSCs) rather than CD11b+ Ly6G+ Ly6Clow polymorphonuclear MDSCs (PMN-MDSCs), but did not affect the immunosuppressive function of MDSCs. Notably, lncRNA Snhg6 could inhibit the expression of EZH2 by ubiquitination pathway at protein level rather than mRNA level during the differentiation of mouse bone marrow cells into MDSCs in vitro. EZH2 may be an important factor in the regulation of lncRNA Snhg6 to promote the differentiation of Mo-MDSCs. So what we found may provide new ideas and targets for anti-tumor immunotherapy targeting MDSCs.

4.
Natl Sci Rev ; 8(7): nwab024, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34691693

RESUMO

Loss-of-function mutations in sorting nexin 14 (SNX14) cause autosomal recessive spinocerebellar ataxia 20, which is a form of early-onset cerebellar ataxia that lacks molecular mechanisms and mouse models. We generated Snx14-deficient mouse models and observed severe motor deficits and cell-autonomous Purkinje cell degeneration. SNX14 deficiency disrupted microtubule organization and mitochondrial transport in axons by destabilizing the microtubule-severing enzyme spastin, which is implicated in dominant hereditary spastic paraplegia with cerebellar ataxia, and compromised axonal integrity and mitochondrial function. Axonal transport disruption and mitochondrial dysfunction further led to degeneration of high-energy-demanding Purkinje cells, which resulted in the pathogenesis of cerebellar ataxia. The antiepileptic drug valproate ameliorated motor deficits and cerebellar degeneration in Snx14-deficient mice via the restoration of mitochondrial transport and function in Purkinje cells. Our study revealed an unprecedented role for SNX14-dependent axonal transport in cerebellar ataxia, demonstrated the convergence of SNX14 and spastin in mitochondrial dysfunction, and suggested valproate as a potential therapeutic agent.

5.
Mol Neurodegener ; 16(1): 66, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551807

RESUMO

BACKGROUND: Aberrant alternative splicing plays critical role in aging and age-related diseases. Heterogeneous nuclear ribonucleoproteins (hnRNPs) reportedly regulate RNA splicing process. Whether and how hnRNPs contribute to age-related neurodegenerative diseases, especially Alzheimer's disease (AD), remain elusive. METHODS: Immunoblotting and immunostaining were performed to determine expression patterns and cellular/subcellular localization of the long isoform of hnRNP D-like (L-DL), which is a hnRNP family member, in mouse hippocampus. Downregulation of L-DL in WT mice was achieved by AAV-mediated shRNA delivery, followed by memory-related behavioural tests. L-DL interactome was analysed by affinity-precipitation and mass spectrometry. Alternative RNA splicing was measured by RNA-seq and analyzed by bioinformatics-based approaches. Downregulation and upregulation of L-DL in APP/PS1 mice were performed using AAV-mediated transduction. RESULTS: We show that L-DL is specifically localized to nuclear speckles. L-DL levels are decreased in the hippocampus of aged mouse brains and downregulation of L-DL impairs cognition in mice. L-DL serves as a structural component to recruit other speckle proteins, and regulates cytoskeleton- and synapse-related gene expression by altering RNA splicing. Mechanistically, these splicing changes are modulated via L-DL-mediated interaction of SF3B3, a core component of U2 snRNP, and U2AF65, a U2 spliceosome protein that guides U2 snRNP's binding to RNA. In addition, L-DL levels are decreased in APP/PS1 mouse brains. While downregulation of L-DL deteriorates memory deficits and overexpression of L-DL improves cognitive function in AD mice, by regulating the alternative splicing and expression of synaptic gene CAMKV. CONCLUSIONS: Our findings define a molecular mechanism by which hnRNP L-DL regulates alternative RNA splicing, and establish a direct role for L-DL in AD-related synaptic dysfunction and memory decline.

6.
Front Immunol ; 12: 696734, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34413850

RESUMO

Bronchial asthma is one of the most chronic pulmonary diseases and major public health problems. In general, asthma prevails in developed countries than developing countries, and its prevalence is increasing in the latter. For instance, the hygiene hypothesis demonstrated that this phenomenon resulted from higher household hygienic standards that decreased the chances of infections, which would subsequently increase the occurrence of allergy. In this review, we attempted to integrate our knowledge with the hygiene hypothesis into beneficial preventive approaches for allergic asthma. Therefore, we highlighted the studies that investigated the correlation between allergic asthma and the two different types of infections that induce the two major antagonizing arms of T cells. This elucidation reflects the association between various types of natural infections and the immune system, which is predicted to support the main objective of the current research on investigating of the benefits of natural infections, regardless their immune pathways for the prevention of allergic asthma. We demonstrated that natural infection with Mycobacterium tuberculosis (Mtb) prevents the development of allergic asthma, thus Bacille Calmette-Guérin (BCG) vaccine is suggested at early age to mediate the same prevention particularly with increasing its efficiency through genetic engineering-based modifications. Likewise, natural helminth infections might inhabit the allergic asthma development. Therefore, helminth-derived proteins at early age are good candidates for designing vaccines for allergic asthma and it requires further investigation. Finally, we recommend imitation of natural infections as a general strategy for preventing allergic asthma that increased dramatically over the past decades.

7.
BMC Med Genomics ; 14(1): 206, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34416878

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is not only a kind of common endocrine syndrome but also a metabolic disorder, which harms the reproductive system and the whole body metabolism of the PCOS patients worldwide. In this study, we aimed to investigate the differences in serum metabolic profiles of the patients with PCOS compared to the healthy controls. MATERIAL AND METHODS: 31 PCOS patients and 31 matched healthy female controls were recruited in this study, the clinical characteristics data were recorded, the laboratory biochemical data were detected. Then, we utilized the metabolomics approach by UPLC-HRMS technology to study the serum metabolic changes between PCOS and controls. RESULTS: The metabolomics analysis showed that there were 68 downregulated and 78 upregulated metabolites in PCOS patients serum compared to those in the controls. These metabolites mainly belong to triacylglycerols, glycerophosphocholines, acylcarnitines, diacylglycerols, peptides, amino acids, glycerophosphoethanolamines and fatty acid. Pathway analysis showed that these metabolites were enriched in pathways including glycerophospholipid metabolism, fatty acid degradation, fatty acid biosynthesis, ether lipid metabolism, etc. Diagnosis value assessed by ROC analysis showed that the changed metabolites, including Leu-Ala/Ile-Ala, 3-(4-Hydroxyphenyl) propionic acid, Ile-Val/Leu-Val, Gly-Val/Val-Gly, aspartic acid, DG(34:2)_DG(16:0/18:2), DG(34:1)_DG(16:0/18:1), Phe-Trp, DG(36:1)_DG(18:0/18:1), Leu-Leu/Leu-Ile, had higher AUC values, indicated a significant role in PCOS. CONCLUSION: The present study characterized the difference of serum metabolites and related pathway profiles in PCOS patients, this finding hopes to provide potential metabolic markers for the prognosis and diagnosis of this disease.

8.
Front Cell Dev Biol ; 9: 669798, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307355

RESUMO

Many neurological disorders exhibit sex differences and sex-specific therapeutic responses. Unfortunately, significant amounts of studies investigating molecular and cellular mechanisms underlying these neurological disorders use primary cell cultures with undetermined sexes; and this may be a source for contradictory results among different studies and impair the validity of study conclusion. Herein, we comprehensively compared sexual dimorphism of gene expression in primary neurons, astrocytes, and microglia derived from neonatal mouse brains. We found that overall sexually dimorphic gene numbers were relatively low in these primary cells, with microglia possessing the most (264 genes), neurons possessing the medium (69 genes), and astrocytes possessing the least (30 genes). KEGG analysis indicated that sexually dimorphic genes in these three cell types were strongly enriched for the immune system and immune-related diseases. Furthermore, we identified that sexually dimorphic genes shared by these primary cells dominantly located on the Y chromosome, including Ddx3y, Eif2s3y, Kdm5d, and Uty. Finally, we demonstrated that overexpression of Eif2s3y increased synaptic transmission specifically in male neurons and caused autism-like behaviors specifically in male mice. Together, our results demonstrate that the sex of primary cells should be considered when these cells are used for studying the molecular mechanism underlying neurological disorders with sex-biased susceptibility, especially those related to immune dysfunction. Moreover, our findings indicate that dysregulation of sexually dimorphic genes on the Y chromosome may also result in autism and possibly other neurological disorders, providing new insights into the genetic driver of sex differences in neurological disorders.

9.
Free Radic Biol Med ; 174: 40-56, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34332078

RESUMO

Oxidative stress damage plays a pivotal role in Parkinson's disease (PD) pathogenesis. Previously, we developed a blood brain barrier-penetrating peptide-based "Trojan Horse" strategy to deliver 4,4'-dimethoxychalcone (DMC) for PD therapy and revealed neuroprotective properties of DMC in a PD model; however, the underlying mechanisms remained unclear. Here, we report that DMC attenuated motor impairment, degeneration of DA neurons and α-synuclein aggregation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and exogenous human α-synuclein-induced PD mouse models. Mechanistically, DMC increased the expression of two critical intermediates in riboflavin metabolism: riboflavin kinase (RFK) and its metabolic product, flavin mononucleotide (FMN). We provide the first direct evidence that FMN ameliorated oxidative stress damage and dopaminergic neuron degeneration both in vitro and in vivo and that riboflavin metabolism was required for DMC-mediated neuroprotection. DMC-induced restoration of redox homeostasis was mediated via the activation of protein kinase Cθ (PKCθ) signaling. Together, our findings reveal that DMC may serve as a novel antioxidant in PD intervention and also define a novel mechanism that underlies its therapeutic activity.


Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Homeostase , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Oxirredução , Doença de Parkinson/tratamento farmacológico , Riboflavina
10.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34156424

RESUMO

Biochemical, pathogenic, and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer's disease (AD) and Down's syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNAseq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with the Fe65-APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization and that lowering GSAP expression reduces pathological effects associated with AD.


Assuntos
Doença de Alzheimer/patologia , Homeostase , Metabolismo dos Lipídeos , Mitocôndrias/metabolismo , Proteínas/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Sequência de Bases , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membranas Mitocondriais/metabolismo , Modelos Biológicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Teste de Campo Aberto , Fosforilação , Ligação Proteica , Transporte Proteico , Proteínas/genética , Transcrição Genética
11.
BMC Med Genomics ; 14(1): 125, 2021 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-33964924

RESUMO

BACKGROUND: The aim of this study was to apply proteomic methodology for the analysis of proteome changes in women with polycystic ovary syndrome (PCOS). MATERIAL AND METHODS: All the participators including 31 PCOS patients and 31 healthy female as controls were recruited, the clinical characteristics data was recorded at the time of recruitment, the laboratory biochemical data was detected. Then, a data-independent acquisition (DIA)-based proteomics method was performed to compare the serum protein changes between PCOS patients and controls. In addition, Western blotting was used to validate the expression of identified proteomic biomarkers. RESULTS: There were 80 proteins differentially expressed between PCOS patients and controls significantly, including 54 downregulated and 26 upregulated proteins. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that downregulated proteins were enriched in platelet degranulation, cell adhesion, cell activation, blood coagulation, hemostasis, defense response and inflammatory response terms; upregulated proteins were enriched in cofactor catabolic process, hydrogen peroxide catabolic process, antioxidant activity, cellular oxidant detoxification, cellular detoxification, antibiotic catabolic process and hydrogen peroxide metabolic process. Receiver operating characteristic curves analysis showed that the area under curve of Histone H4 (H4), Histone H2A (H2A), Trem-like transcript 1 protein (TLT-1) were all over than 0.9, indicated promising diagnosis values of these proteins. Western blotting results proved that the detected significant proteins, including H4, H2A, TLT-1, Peroxiredoxin-1, Band 3 anion transport protein were all differently expressed in PCOS and control groups significantly. CONCLUSION: These proteomic biomarkers provided the potentiality to help us understand PCOS better, but future studies comparing systemic expression and exact role of these candidate biomarkers in PCOS are essential for confirmation of this hypothesis.

12.
J Immunol Res ; 2021: 5548463, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33987447

RESUMO

Signaling lymphocytic activation molecule (SLAM) and SLAM-associated protein (SAP) play important role in inflammatory and autoimmune diseases. Our study is aimed at detecting the expression of SLAM and SAP in patients with Graves' disease (GD) and analyzing the effect of SLAM/SAP on circulating blood CD4+CXCR5+Foxp3+ follicular regulatory T (Tfr) cells. The level of SAP in CD4+CXCR5+ T cells and the level of SLAM on CD19+ B cells were significantly increased in the patients with GD, but no significant difference in the level of SLAM on CD4+CXCR5+ T cells was observed between the patients with GD and the healthy controls. A decrease in the percentage of Foxp3+ cells in CD4+CXCR5+ T cells was observed following anti-SLAM treatment, but the percentages of IFN-γ + cells, IL-4+ cells, and IL-17+ cells showed no obvious differences. The proportion of circulating Tfr cells was decreased in the patients with GD, and the proportion of circulating Tfr cells had a negative correlation with the level of SAP in CD4+CXCR5+ T cells and the levels of autoantibodies in the serum of the patients with GD. Our results suggested that the SLAM/SAP signaling pathway is involved in the decrease of circulating Tfr cells in Graves' disease.


Assuntos
Doença de Graves/imunologia , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Linfócitos T Reguladores/imunologia , Adulto , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Feminino , Doença de Graves/sangue , Voluntários Saudáveis , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/imunologia , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/análise , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/análise , Linfócitos T Reguladores/metabolismo
13.
J Leukoc Biol ; 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34013598

RESUMO

B10 cells play negative roles in inflammatory disorders by producing IL-10. However, their effects on fibrosis have not been elucidated. Therefore, this study was conducted to examine the dynamic changes of B10 cell frequency and their potential role in cardiac fibrosis. We found that the frequency of B10 cells was significantly increased, and they participated in the regression of fibrosis via IL-10, particularly by accelerating hyaluronan secretion and inhibiting collagen deposition. In vivo, hyaluronan ablation or treatment significantly restricted cardiac fibrosis development. hyaluronan-induced conversion of M1/M2 Mc was dependent on the size of hyaluronan. Low molecular weight hyaluronan promoted the conversion to M1 Mϕ, whereas medium and high molecular weight hyaluronan accelerated Mϕ transdifferentiation into the M2 phenotype. Adoptive transfer of B10 cells significantly attenuated collagen deposition whereas CD19-/- mice with reduced B10 cells exacerbated fibrosis following cardiac injury. Our results provide new evidence suggesting that B10 cells exert antifibrotic effects by regulating the extracellular matrix composition during cardiac injury, and also highlight that B10 cells may serve as a promising therapeutic candidate for managing cardiac fibrosis-associated disorders.

14.
Front Immunol ; 12: 633796, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841415

RESUMO

Triggering receptor expressed on myeloid cells-2 (TREM2) and colony-stimulating factor 1 receptor (CSF1R) are crucial molecules for microgliopathy, which is characterized by microglia dysfunction and has recently been proposed as the neuropathological hallmark of neurological disorders. TREM2 and CSF1R are receptors expressed primarily in microglia in the brain and modulate microglial activation and survival. They are thought to be in close physical proximity. However, whether there is a direct interaction between these receptors remains elusive. Moreover, the physiological role and mechanism of the interaction of TREM2 and CSF1R remain to be determined. Here, we found that TREM2 interacted with CSF1R based on a co-immunoprecipitation assay. Additionally, we found that CSF1R knockdown significantly reduced the survival of primary microglia and increased the Trem2 mRNA level. In contrast, CSF1R expression was increased in Trem2-deficient microglia. Interestingly, administration of CSF1, the ligand of CSF1R, partially restored the survival of Trem2-deficient microglia in vitro and in vivo. Furthermore, CSF1 ameliorated Aß plaques deposition in Trem2 -/-; 5XFAD mouse brain. These findings provide solid evidence that TREM2 and CSF1R have intrinsic abilities to form complexes and mutually modulate their expression. These findings also indicate the potential role of CSF1 in therapeutic intervention in TREM2 variant-bearing patients with a high risk of Alzheimer's disease (AD).


Assuntos
Sobrevivência Celular , Glicoproteínas de Membrana/metabolismo , Microglia/fisiologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores Imunológicos/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Imunoprecipitação , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia
15.
J Asthma Allergy ; 14: 361-369, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33880041

RESUMO

Background: Allergic rhinitis (AR) is characterized by type I hypersensitivity that is mediated by IgE-induced humoral responses. Follicular helper T cells (Tfh) comprise the key helper T cell (Th) subset that promotes antibody production. Signaling lymphocytic activation molecules (SLAMs) participate in regulation of the differentiation and function of Tfh cells, but whether this regulation is involved in the pathogenesis of AR is unknown. Methods: CD4+CXCR5+ Tfh-like cells from peripheral blood were detected by flow cytometry. The IL-21 and IgE levels in serum were measured by an ELISA. Blood CD4+CXCR5+ Tfh-like cells were sorted and cultured with anti-SLAM mAb in vitro. Results: The frequencies of circulating CD4+CXCR5+ Tfh-like cells appeared virtually unchanged in AR patients, but the expression of SLAMs and SLAM-associated protein (SAP) on circulating Tfh-like cells was significantly decreased. Meanwhile, the level of serum IL-21 was increased in AR patients, and a negative correlation was found between the IL-21 level and SLAM or SAP expression on CD4+CXCR5+ T cells. Treatment with anti-SLAM mAb resulted in reduced IL-21 production by Tfh-like cells in vitro. Additionally, SLAM expression on B cells was significantly decreased, although the percentages of B cells were increased in AR patients. Conclusion: SLAMs negatively regulate IL-21 production in CD4+CXCR5+ Tfh-like cells, which contributes to the pathogenesis of AR.

16.
Front Immunol ; 12: 649020, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717204

RESUMO

Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous cells derived from the bone marrow and they are the major component of the tumor-induced immunosuppressive environment. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, catalyzes the polyubiquitination of target proteins. TRAF6 plays a critical role in modulating the immune system. However, whether TRAF6 is involved in the regulation of MDSCs has not been thoroughly elucidated to date. In this study, we found that the expression of TRAF6 in MDSCs derived from tumor tissue was significantly upregulated compared with that of MDSCs from spleen of tumor-bearing mice. Knockdown of TRAF6 remarkably attenuated the immunosuppressive effects of MDSCs. Mechanistically, TRAF6 might improve the immunosuppression of MDSCs by mediating K63-linked polyubiquitination and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Additionally, it was discovered that the accumulation of MDSCs was abnormal in peripheral blood of lung cancer patients. TRAF6 and arginase 1 were highly expressed in MDSCs of patients with lung cancer. Taken together, our study demonstrated that TRAF6 participates in promoting the immunosuppressive function of MDSCs and provided a potential target for antitumor immunotherapy.


Assuntos
Tolerância Imunológica/imunologia , Neoplasias Pulmonares/imunologia , Células Supressoras Mieloides/imunologia , Fator 6 Associado a Receptor de TNF/imunologia , Animais , Arginase/genética , Arginase/imunologia , Arginase/metabolismo , Western Blotting , Linhagem Celular Tumoral , Células Cultivadas , Expressão Gênica/imunologia , Humanos , Tolerância Imunológica/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/metabolismo , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo
17.
J Cell Mol Med ; 25(9): 4516-4521, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33783963

RESUMO

Both Colony-stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells-2 (TREM2) are trans-membrane receptors and are expressed in the brain primarily by microglia. Mutations in these two microglia-expressed genes associated with neurodegenerative disease have recently been grouped under the term "microgliopathy". Several literatures have indicated that CSF1R and TREM2 encounters a stepwise shedding and TREM2 variants impair or accelerate the processing. However, whether CSF1R variant affects the shedding of CSF1R remains elusive. Here, plasmids containing human CSF1R or TREM2 were transiently transfected into the human embryonic kidney (HEK) 293T cells. Using Western Blot and/or ELISA assay, we demonstrated that, similar to those of TREM2, an N-terminal fragment (NTF) shedding of CSF1R ectodomain and a subsequent C-terminal fragment (CTF) of CSF1R intra-membrane were generated by a disintegrin and metalloprotease (ADAM) family member and by γ-secretase, respectively. And the shedding was inhibited by treatment with Batimastat, an ADAM inhibitor, or DAPT or compound E, a γ-secretase inhibitor. Importantly, we show that the cleaved fragments, both extracellular domain and intracellular domain of a common disease associated I794T variant, were decreased significantly. Together, our studies demonstrate a stepwise approach of human CSF1R cleavage and contribute to understand the pathogenicity of CSF1R I794T variant in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). These studies also suggest that the cleaved ectodomain fragment released from CSF1R may be proposed as a diagnostic biomarker for ALSP.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Leucoencefalopatias/patologia , Glicoproteínas de Membrana/metabolismo , Proteínas Mutantes/metabolismo , Mutação , Proteólise , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores Imunológicos/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Células HEK293 , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Glicoproteínas de Membrana/genética , Proteínas Mutantes/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores Imunológicos/genética
18.
Life Sci ; 270: 119142, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524419

RESUMO

Adeno-associated virus (AAV) vector, an excellent gene therapy vector, has been widely used in the treatment of various central nervous system (CNS) diseases. Due to the presence of the blood-brain barrier (BBB), early attempts at AAV-based CNS diseases treatment were mainly performed through intracranial injections. Subsequently, systemic injections of AAV9, the first AAV that was shown to have BBB-crossing ability in newborn and adult mice, were assessed in clinical trials for multiple CNS diseases. However, the development of systemic AAV injections to treat CNS diseases is still associated with many challenges, such as the efficiency of AAV in crossing the BBB, the peripheral toxicity caused by the expression of AAV-delivered genes, and the immune barrier against AAV in the blood. In this review, we will introduce the biology of the AAV vector and the advantages of systemic AAV injections to treat CNS diseases. Most importantly, we will introduce the challenges associated with systemic injection of therapeutic AAV in treating CNS diseases and suggest feasible solutions.


Assuntos
Doenças do Sistema Nervoso Central/terapia , Dependovirus/genética , Terapia Genética/métodos , Absorção Fisiológica , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Linhagem Celular , Doenças do Sistema Nervoso Central/genética , Dependovirus/metabolismo , Técnicas de Transferência de Genes/efeitos adversos , Terapia Genética/tendências , Vetores Genéticos/genética , Humanos , Camundongos , Transdução Genética/métodos , Transgenes
19.
Sci Adv ; 7(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33523861

RESUMO

Down syndrome (DS), caused by trisomy of chromosome 21, is the most significant risk factor for early-onset Alzheimer's disease (AD); however, underlying mechanisms linking DS and AD remain unclear. Here, we show that triplication of homologous chromosome 21 genes aggravates neuroinflammation in combined murine DS-AD models. Overexpression of USP25, a deubiquitinating enzyme encoded by chromosome 21, results in microglial activation and induces synaptic and cognitive deficits, whereas genetic ablation of Usp25 reduces neuroinflammation and rescues synaptic and cognitive function in 5×FAD mice. Mechanistically, USP25 deficiency attenuates microglia-mediated proinflammatory cytokine overproduction and synapse elimination. Inhibition of USP25 reestablishes homeostatic microglial signatures and restores synaptic and cognitive function in 5×FAD mice. In summary, we demonstrate an unprecedented role for trisomy 21 and pathogenic effects associated with microgliosis as a result of the increased USP25 dosage, implicating USP25 as a therapeutic target for neuroinflammation in DS and AD.

20.
Cell Mol Immunol ; 18(2): 440-451, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33408339

RESUMO

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by progressive inflammation and tissue damage in salivary glands and lacrimal glands. Our previous studies showed that myeloid-derived suppressor cells (MDSCs) exhibited impaired immunosuppressive function during disease progression in patients with SS and mice with experimental Sjögren's syndrome (ESS), but it remains unclear whether restoring the function of MDSCs can effectively ameliorate the development of ESS. In this study, we found that murine olfactory ecto-mesenchymal stem cell-derived exosomes (OE-MSC-Exos) significantly enhanced the suppressive function of MDSCs by upregulating arginase expression and increasing ROS and NO levels. Moreover, treatment with OE-MSC-Exos via intravenous injection markedly attenuated disease progression and restored MDSC function in ESS mice. Mechanistically, OE-MSC-Exo-secreted IL-6 activated the Jak2/Stat3 pathway in MDSCs. In addition, the abundant S100A4 in OE-MSC-Exos acted as a key factor in mediating the endogenous production of IL-6 by MDSCs via TLR4 signaling, indicating an autocrine pathway of MDSC functional modulation by IL-6. Taken together, our results demonstrated that OE-MSC-Exos possess therapeutic potential to attenuate ESS progression by enhancing the immunosuppressive function of MDSCs, possibly constituting a new strategy for the treatment of Sjögren's syndrome and other autoimmune diseases.

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