RESUMO
Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.
Assuntos
Doenças Autoimunes , Mieloma Múltiplo , Doenças Musculares , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B , Doenças Neuroinflamatórias , Imunoterapia Adotiva , Doenças Autoimunes/terapia , Autoanticorpos , Doenças Musculares/terapia , Análise de Célula Única , Terapia Baseada em Transplante de Células e Tecidos , Microambiente TumoralRESUMO
Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.
Assuntos
Doenças Desmielinizantes , Microglia , Camundongos , Animais , Microglia/metabolismo , Ácido Linoleico/metabolismo , Autofagia , Doenças Desmielinizantes/metabolismo , RegeneraçãoRESUMO
Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.
Assuntos
Doença de Alzheimer , Neuromielite Óptica , Animais , Camundongos , Humanos , Microglia/metabolismo , Doença de Alzheimer/metabolismo , Neuromielite Óptica/genética , Neuromielite Óptica/metabolismo , Doenças Neuroinflamatórias , Biomarcadores/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/genéticaRESUMO
Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Isquemia Encefálica , Substância Branca , Animais , Masculino , Camundongos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Isquemia Encefálica/metabolismo , Doença Crônica , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Substância Branca/efeitos dos fármacos , Substância Branca/patologia , Substância Branca/metabolismoRESUMO
The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage.
Assuntos
Barreira Hematoencefálica , Isquemia Encefálica , Lipoproteínas LDL , Microglia , Substância Branca , Microglia/metabolismo , Animais , Substância Branca/metabolismo , Substância Branca/patologia , Camundongos , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , Isquemia Encefálica/metabolismo , Barreira Hematoencefálica/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Fagocitose/fisiologia , Bainha de Mielina/metabolismoRESUMO
Chronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is expressed exclusively on microglia in the central nervous system (CNS), plays an essential role in microglial response in various CNS disorders. However, the specific role of Trem2 in chronic cerebral hypoperfusion has not been elucidated. In this study, we investigated the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). Our results showed that chronic hypoperfusion induced white matter demyelination, microglial phagocytosis, and activation of the microglial autophagic-lysosomal pathway, accompanied by an increase in Trem2 expression. After Trem2 knockout, we observed attenuation of white matter lesions and microglial response. Trem2 deficiency also suppressed microglial phagocytosis and relieved activation of the autophagic-lysosomal pathway, leading to microglial polarization towards anti-inflammatory and homeostatic phenotypes. Furthermore, Trem2 knockout inhibited lipid droplet accumulation in microglia in vitro. Collectively, these findings suggest that Trem2 deficiency ameliorated microglial phagocytosis and autophagic-lysosomal activation in hypoperfusion-induced white matter injury, and could be a promising target for the treatment of chronic cerebral hypoperfusion.
Assuntos
Isquemia Encefálica , Doenças Desmielinizantes , Substância Branca , Animais , Camundongos , Substância Branca/patologia , Microglia/metabolismo , Fagocitose , Isquemia Encefálica/metabolismo , Lisossomos/metabolismo , Doenças Desmielinizantes/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are activated and play a pivotal role in response to tissue injury. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by microglia and promotes microglial activation, survival and phagocytosis. Here, we identify a critical role for TREM2 in microglial activation and function during AQP4-IgG and complement-induced demyelination. TREM2-deficient mice had more severe tissue damage and neurological impairment, as well as fewer oligodendrocytes with suppressed proliferation and maturation. The number of microglia clustering in NMOSD lesions and their proliferation were reduced in TREM2-deficient mice. Moreover, morphology analysis and expression of classic markers showed compromised activation of microglia in TREM2-deficient mice, which was accompanied by suppressed phagocytosis and degradation of myelin debris by microglia. These results overall indicate that TREM2 is a key regulator of microglial activation and exert neuroprotective effects in NMOSD demyelination.
Assuntos
Glicoproteínas de Membrana , Microglia , Neuromielite Óptica , Receptores Imunológicos , Animais , Camundongos , Sistema Nervoso Central , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Bainha de Mielina/metabolismo , Neuromielite Óptica/metabolismo , Fagocitose/genética , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
BACKGROUND: Identifying sarcopenia's causally associated plasma proteins would provide potential therapeutic targets. METHODS: We screened out sarcopenia-related proteins with genome-wide association studies (GWAS) summary data and cis-protein loci genetic instruments. Summary data of sarcopenia were obtained from a GWAS of 256,523 Europeans aged 60 years and over. The causal effects of the proteins were investigated by cis-Mendelian Randomisation (MR) and multiverse sensitivity analysis. We also explored the robust proteins' causal associations with appendicular lean mass (ALM) and surveyed their druggability and clinical development activities. RESULTS: In sum, 60 proteins from plasma proteome analysis studies and 12 from other studies were enrolled for MR analysis. In the whole population, four proteins (HPT, AT1B2, ISLR2 and TNF12) showed causal associations with the risk of sarcopenia according to the European Working Group on Sarcopenia in Older People (EWGSOP) criterion. In the female population, AT1B2 and TNFSF12 revealed causal associations with sarcopenia risk according to the EWGSOP criterion; HGF revealed a negative association according to the National Institutes of Health criterion. All of them were druggable, and the inhibitors of TNF12 and HGF were evaluated in clinical trials for other diseases. TNF12 also revealed a negative causal association with ALM, whereas HGF was positively causally associated with ALM. CONCLUSIONS: Five druggable plasma proteins revealed causal associations with sarcopenia in the whole or female populations. TNF12 and HGF were the targets of therapeutic agents evaluated in clinical trials, and they were also causally associated with ALM. Our study suggested the potential mechanisms and therapeutic targets for sarcopenia.
Assuntos
Sarcopenia , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Sarcopenia/diagnóstico , Sarcopenia/tratamento farmacológico , Sarcopenia/genética , Estudo de Associação Genômica Ampla , Composição Corporal , Inquéritos e Questionários , Proteínas SanguíneasRESUMO
BACKGROUND: Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been described as a biomarker for microglial activation, which were observed increased in a variety of neurological disorders. OBJECTIVE: Our objective was to explore whether genetically determined CSF sTREM2 levels are causally associated with different neurological diseases by conducting a two-sample Mendelian randomization (MR) study. METHODS: Single nucleotide polymorphisms significantly associated with CSF sTREM2 levels were selected as instrumental variables to estimate the causal effects on clinically common neurological diseases, including stroke, Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy and their subtypes. Summary-level statistics of both exposure and outcomes were applied in an MR framework. RESULTS: Genetically predicted per 1 pg/dL increase of CSF sTREM2 levels was associated with higher risk of multiple sclerosis (OR = 1.038, 95%CI = 1.014-1.064, p = 0.002). Null association was found in risk of other included neurological disorders. CONCLUSIONS: These findings provide support for a potential causal relationship between elevated CSF sTREM2 levels and higher risk of multiple sclerosis.
Assuntos
Doença de Alzheimer , Glicoproteínas de Membrana , Doenças do Sistema Nervoso , Receptores Imunológicos , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Humanos , Glicoproteínas de Membrana/líquido cefalorraquidiano , Análise da Randomização Mendeliana , Doenças do Sistema Nervoso/genéticaRESUMO
PURPOSE: To determine the role of vaginal microbiota in the efficacy of cervical cerclage in obstetric outcomes of twin pregnancies. METHODS: This retrospective study enrolled 68 twin pregnant women diagnosed with cervical incompetence (CIC) and 68 twin pregnancies without CIC. The CIC group was further divided into two subgroups: cerclage group (n = 51) and non-cerclage group (n = 17), according to whether cervical cerclage was performed in the second trimester. Data of vaginal microbiota and obstetric outcomes were collected and compared. RESULTS: Cervical incompetence had harmful effect on both pregnancy outcomes and vaginal microecology, characterized by earlier gestational week at delivery (30.3 ± 5.6 vs 35.6 ± 1.1, P < 0.001), a lower birth weight of newborns (OR 0.40; 95% CI 0.22-0.74), a higher vaginal pH value (OR 0.11; 95% CI 0.04-0.30) and a lower abundance of Lactobacillus (OR 0.34; 95% CI 0.17-0.70). In addition, compared with the vaginal microbiota after cerclage, less normal diversity of bacterial flora (OR 0.35; 95% CI 0.12-1.01), less Lactobacillus (OR 0.40; 95% CI 0.18-0.91) and more Gardnerella vaginalis (OR 18.92; 95% CI 2.38-150.35) appeared before cerclage. Besides, the unhealthy vaginal environment also had an unfavorable influence on the neonatal outcomes, increased neonatal mortality rate was observed in the group of vaginal pH > 4.5 (P < 0.05). Fortunately, compared with the non-cerclage group, the cerclage group had a longer interval from diagnosis to delivery (≥ 8 weeks) and more of the newborns' birth weight were not less than 1500 g (P < 0.05). CONCLUSION: A healthy vaginal environment is essential to improve the obstetric outcome for twin pregnancies with cervical cerclage.
Assuntos
Cerclagem Cervical , Microbiota , Nascimento Prematuro , Incompetência do Colo do Útero , Feminino , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez , Gravidez de Gêmeos , Nascimento Prematuro/prevenção & controle , Estudos Retrospectivos , Incompetência do Colo do Útero/cirurgiaRESUMO
In response to various types of environmental and cellular stress, microglia rapidly activate and exhibit either pro- or anti-inflammatory phenotypes to maintain tissue homeostasis. Activation of microglia can result in changes in morphology, phagocytosis capacity, and secretion of cytokines. Furthermore, microglial activation also induces changes to cellular energy demand, which is dependent on the metabolism of various metabolic substrates including glucose, fatty acids, and amino acids. Accumulating evidence demonstrates metabolic reprogramming acts as a key driver of microglial immune response. For instance, microglia in pro-inflammatory states preferentially use glycolysis for energy production, whereas, cells in anti-inflammatory states are mainly powered by oxidative phosphorylation and fatty acid oxidation. In this review, we summarize recent findings regarding microglial metabolic pathways under physiological and pathological circumtances. We will then discuss how metabolic reprogramming can orchestrate microglial response to a variety of central nervous system pathologies. Finally, we highlight how manipulating metabolic pathways can reprogram microglia towards beneficial functions, and illustrate the therapeutic potential for inflammation-related neurological diseases.
Assuntos
Adaptação Fisiológica/fisiologia , Reprogramação Celular/fisiologia , Sistema Nervoso Central/metabolismo , Microglia/metabolismo , Animais , Sistema Nervoso Central/imunologia , Humanos , Metaboloma , Microglia/imunologia , FenótipoRESUMO
Since microglia-associated neuroinflammation plays a pivotal role in the progression of white matter diseases, modulating microglial activation has been suggested as a potential therapeutic strategy. Here, we investigated the anti-inflammatory effects of fingolimod (FTY720) on microglia and analyzed the crosstalk between microglia autophagy and neuroinflammation. Lipopolysaccharide (LPS)-induced primary cultured microglia model was established. Microglial phenotypes were assessed by Western blot, quantitative real-time polymerase chain reaction (RT-PCR) and flow cytometry. Autophagy was evaluated by immunofluorescence, MDC staining and Western blot. Rapamycin was used to investigate the role of autophagic process in regulating microglial phenotypes. The signaling markers were screened by RT-PCR and Western blot. FTY720 shifted microglial phenotype from pro-inflammatory state to anti-inflammatory state and inhibited microglial autophagy under lipopolysaccharide (LPS) treatment. Rapamycin reversed the effect of FTY720 on phenotype transformation of microglia. The results of mechanism studies have shown that FTY720 notably repressed LPS-induced STAT1 activity, which was reactivated by rapamycin. Our research suggested that FTY720 could significantly transform pro-inflammatory microglia into anti-inflammatory microglia by suppressing autophagy via STAT1.
Assuntos
Anti-Inflamatórios/farmacologia , Autofagia , Cloridrato de Fingolimode/farmacologia , Microglia/metabolismo , Microglia/patologia , Fator de Transcrição STAT1/metabolismo , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Inflamação/patologia , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Modelos Biológicos , Fenótipo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: Information on stroke survivors infected with coronavirus disease 2019 (COVID-19) is limited. The aim of this study was to describe specific clinical characteristics and outcomes of patients with COVID-19 with a history of stroke. METHODS: All the confirmed cases of COVID-19 at Tongji Hospital from January 27 to March 5, 2020, were included in our cohort study. Clinical data were analyzed and compared between patients with and without a history of stroke. RESULTS: Of the included 1875 patients with COVID-19, 50 patients had a history of stroke. The COVID-19 patients with medical history of stroke were older with more comorbidities, had higher neutrophil count, and lower lymphocyte and platelet counts than those without history of stroke. The levels of D-dimers, cardiac troponin I, NT pro-brain natriuretic peptide, and interleukin-6 were also markedly higher in patients with history of stroke. Stroke survivors who underwent COVID-19 developed more acute respiratory distress syndrome and received more noninvasive mechanical ventilation. Data from propensity-matched analysis indicated a higher proportion of patients with COVD-19 with a history of stroke were admitted to the intensive care unit requiring mechanical ventilation and were more likely to be held in the unit or die, compared with non-stroke history COVID-19 patients. CONCLUSIONS: Patients with COVID-19 with a history of stroke had more severe clinical symptoms and poorer outcomes compared with those without a history of stroke.
Assuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Acidente Vascular Cerebral/epidemiologia , Idoso , Contagem de Células Sanguíneas , COVID-19 , China/epidemiologia , Comorbidade , Infecções por Coronavirus/epidemiologia , Feminino , Mortalidade Hospitalar , Hospitais Universitários/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/epidemiologia , Utilização de Procedimentos e Técnicas , Pontuação de Propensão , Recidiva , Respiração Artificial/estatística & dados numéricos , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , SARS-CoV-2 , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/terapia , Resultado do TratamentoRESUMO
BACKGROUND: In December 2019, coronavirus 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China. METHODS: Demographic and clinical data of all confirmed cases with COVID-19 on admission at Tongji Hospital from 10 January to 12 February 2020 were collected and analyzed. The data on laboratory examinations, including peripheral lymphocyte subsets, were analyzed and compared between patients with severe and nonsevere infection. RESULTS: Of the 452 patients with COVID-19 recruited, 286 were diagnosed as having severe infection. The median age was 58 years and 235 were male. The most common symptoms were fever, shortness of breath, expectoration, fatigue, dry cough, and myalgia. Severe cases tend to have lower lymphocyte counts, higher leukocyte counts and neutrophil-lymphocyte ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most severe cases demonstrated elevated levels of infection-related biomarkers and inflammatory cytokines. The number of T cells significantly decreased, and were more impaired in severe cases. Both helper T (Th) cells and suppressor T cells in patients with COVID-19 were below normal levels, with lower levels of Th cells in the severe group. The percentage of naive Th cells increased and memory Th cells decreased in severe cases. Patients with COVID-19 also have lower levels of regulatory T cells, which are more obviously decreased in severe cases. CONCLUSIONS: The novel coronavirus might mainly act on lymphocytes, especially T lymphocytes. Surveillance of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis, and treatment of COVID-19.
Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , China , Infecções por Coronavirus/virologia , Tosse/imunologia , Tosse/virologia , Estado Terminal , Citocinas/imunologia , Feminino , Febre/imunologia , Febre/virologia , Hospitalização , Humanos , Contagem de Leucócitos , Linfócitos/imunologia , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/virologia , Neutrófilos/imunologia , Neutrófilos/virologia , Pandemias , Pneumonia Viral/virologia , Estudos Retrospectivos , SARS-CoV-2 , Adulto JovemRESUMO
BACKGROUND: Multiple sclerosis (MS) is an immune-mediated demyelinated disease of the central nervous system. Activation of microglia is involved in the pathogenesis of myelin loss. OBJECTIVE: This study is focused on the role of Hv1 in regulating demyelination and microglial activation through reactive oxygen species (ROS) production after lysophosphatidylcholine (LPC)-mediated demyelination. We also explored autophagy in this process. METHODS: A model of demyelination using two-point LPC injection into the corpus callosum was established. LFB staining, immunofluorescence, Western blot, and electron microscopy were used to study the severity of demyelination. Microglial phenotype and autophagy were detected by immunofluorescence and Western blot. Morris water maze was used to test spatial learning and memory ability. RESULTS: We have identified that LPC-mediated myelin damage was reduced by Hv1 deficiency. Furthermore, we found that ROS and autophagy of microglia increased in the demyelination region, which was also inhibited by Hv1 knockout. CONCLUSION: These results suggested that microglial Hv1 deficiency ameliorates demyelination through inhibition of ROS-mediated autophagy and microglial phenotypic transformation.
Assuntos
Autofagia/fisiologia , Doenças Desmielinizantes/metabolismo , Canais Iônicos/deficiência , Lisofosfatidilcolinas/toxicidade , Microglia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Autofagia/efeitos dos fármacos , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/patologiaRESUMO
BACKGROUND: Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Proteins associated with acute LVO pathogenesis and endothelial function may appear in blood samples of AIS patients due to LVO, thus permitting development of blood-based biomarkers for its diagnosis and prognosis. METHODS: This study is a single-center, retrospective, observational case-control trial. Consecutive patients who presented at the Department of Neurology of Tongji Hospital were recruited from July 2016 to April 2018. In the discovery phase, a proteomic approach with iTRAQ-based LC-MS/MS was used to investigate the altered proteomic pattern in plasma from patients with AIS due to LVO. In the validation study, Western blots was used to identify biomarkers associated with stroke diagnosis as well as their prognostic value associated with different collateral statuses. RESULTS: For this exploratory study, the proteomic analysis of plasma from 40 patients with AIS due to LVO and 20 healthy controls revealed seven differentially expressed proteins with a 1.2/0.83-fold or greater difference between groups. The four elevated proteins, PPBP (1.58 ± 0.78 vs 0.98 ± 0.37; P < 0.001), THBS1 (1.13 ± 0.88 vs 0.43 ± 0.26; P < 0.001), LYVE1 (1.61 ± 0.55 vs 0.97 ± 0.50; P < 0.001), and IGF2 (1.19 ± 0.42 vs 0.86 ± 0.24; P < 0.001), were verified by Western blots analysis in an independent cohort including 33 patients and 33 controls. A strong interaction was observed between the four-protein panel and the diagnosis of AIS due to LVO (AUC 0.947; P < 0.001). Furthermore, IGF2, LYVE1, and THBS1 were closely associated with collateral status (IGF2 0.115, 95% CI 0.016-0.841, P = 0.033; LYVE1 0.183, 95% CI 0.036-0.918, P = 0.039; THBS1 4.257, 95% CI 1.273-14.228, P = 0.019), and proved to be independent predictors of good outcome (IGF2 0.115, 95% CI 0.015-0.866, P = 0.036; LYVE1 0.028, 95% CI 0.002-0.334, P = 0.005; THBS1 3.294, 95% CI 1.158-9.372, P = 0.025) at a 3-month follow-up. CONCLUSIONS: The identified 4-biomarker panel could provide diagnostic aid to the existing imaging modalities for AIS due to LVO, and the prognostic value of IGF2, LYVE1, and THBS1 was proved in predicting functional outcomes related to collateral status. Trial registration ClinicalTrials.gov NCT03122002. Retrospectively registered April 20, 2017. URL of trial registry record: https://www.clinicaltrials.gov/ct2/show/NCT03122002?term=NCT+03122002&rank=1.
Assuntos
Biomarcadores/sangue , Isquemia Encefálica/sangue , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/complicações , Proteômica/métodos , Acidente Vascular Cerebral/sangue , Adulto , Idoso , Biomarcadores/análise , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/metabolismo , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Estudos de Casos e Controles , Transtornos Cerebrovasculares/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismoRESUMO
Background: White matter microstructure is valued for being an indicator of neural network integrity, which plays an indispensable role in the execution of advanced brain functions. Although the number of publications has increased in the past 10 years, no comprehensive analysis has yet been conducted of this field. Therefore, this study aimed to identify the research hotspots and trends in research on white matter microstructure using a bibliometric analysis of the related literature published from 2013 to 2022. Methods: VOSviewer and CiteSpace were used to objectively analyze the research articles concerning white matter microstructure, which were retrieved from the Web of Science Core Collection (WoSCC). Results: A total of 5,806 publications were obtained, with the number of published articles increasing annually over the past decade. The United States, China, the United Kingdom, and Canada maintained the top positions worldwide and had strong cooperative relationships. The top institution and journal were Harvard Medical School and Neuroimage, respectively. Alexander Leemans, Marek Kubicki, and Martha E Shenton were the most productive authors. Thematic keywords mainly included "diffusion tensor imaging" (DTI), "white matter integrity", and "connectivity". The keyword analysis revealed that DTI has a critical role in detecting white matter microstructure integrity and that fractional anisotropy is the main parameter in the assessment process. Keyword burst detection identified four research hotspots: movement, distortion correction, voxelwise analysis, and fixel-based analysis. Conclusions: This bibliometric analysis provided a systematic understanding of the research on white matter microstructure and identified the current frontiers. This may help clinicians and researchers comprehensively identify hotspots and trends in this field.
RESUMO
Background: Growing evidence links immunological responses to Multiple sclerosis (MS), but specific immune factors are still unclear. Methods: Mendelian randomization (MR) was performed to investigate the association between peripheral hematological traits, MS risk, and its severity. Then, further subgroup analysis of immune counts and circulating cytokines and growth factors were performed. Results: MR revealed higher white blood cell count (OR [95%CI] = 1.26 [1.10,1.44], P = 1.12E-03, P adjust = 3.35E-03) and lymphocyte count (OR [95%CI] = 1.31 [1.15,1.50], P = 5.37E-05, P adjust = 3.22E-04) increased the risk of MS. In further analysis, higher T cell absolute count (OR [95%CI] = 2.04 [1.36,3.08], P = 6.37E-04, P adjust = 2.19E-02) and CD4+ T cell absolute count (OR [95%CI] = 2.11 [1.37,3.24], P = 6.37E-04, P adjust = 2.19E-02), could increase MS risk. While increasing CD25++CD4+ T cell absolute count (OR [95%CI] = 0.75 [0.66,0.86], P = 2.12E-05, P adjust = 1.72E-03), CD25++CD4+ T cell in T cell (OR [95%CI] = 0.79[0.70,0.89], P = 8.54E-05, P adjust = 5.29E-03), CD25++CD4+ T cell in CD4+ T cell (OR [95%CI] = 0.80[0.72,0.89], P = 1.85E-05, P adjust = 1.72E-03), and CD25++CD8+ T cell in T cell (OR [95%CI] = 0.68[0.57,0.81], P = 2.22E-05, P adjust = 1.72E-03), were proved to be causally defensive for MS. For the disease severity, the suggestive association between some traits related to CD4+ T cell, Tregs and MS severity were demonstrated. Moreover, elevated levels of IL-2Ra had a detrimental effect on the risk of MS (OR [95%CI] = 1.22 [1.12,1.32], P = 3.20E-06, P adjust = 1.34E-04). Conclusions: This study demonstrated a genetically predicted causal relationship between elevated peripheral immune cell counts and MS. Subgroup analysis revealed a specific contribution of peripheral immune cells, holding potential for further investigations into the underlying mechanisms of MS and its severity.
Assuntos
Esclerose Múltipla , Humanos , Esclerose Múltipla/genética , Gravidade do Paciente , Linfócitos T CD8-Positivos , Causalidade , Contagem de CélulasRESUMO
Microglia, the major resident immune cells in the central nervous system, serve as the frontline soldiers against cerebral ischemic injuries, possibly along with metabolic alterations. However, signaling pathways involved in the regulation of microglial immunometabolism in ischemic stroke remain to be further elucidated. In this study, using single-nuclei RNA sequencing, a microglial subcluster up-regulated in ischemic brain tissues is identified, with high expression of Igf1 and Trem2, neuroprotective transcriptional signature and enhanced oxidative phosphorylation. Microglial depletion by PLX3397 exacerbates ischemic brain damage, which is reversed by repopulating the microglia with high Igf1 and Trem2 phenotype. Mechanistically, Igf1 serves as one of the major down-stream molecules of Trem2, and Trem2-Igf1 signaling axis regulates microglial functional and metabolic profiles, exerting neuroprotective effects on ischemic stroke. Overexpression of Igf1 and supplementation of cyclocreatine restore microglial glucometabolic levels and cellular functions even in the absence of Trem2. These findings suggest that Trem2-Igf1 signaling axis reprograms microglial immunometabolic profiles and shifts microglia toward a neuroprotective phenotype, which has promising therapeutic potential in treating ischemic stroke.
Assuntos
AVC Isquêmico , Fármacos Neuroprotetores , Humanos , Microglia/metabolismo , AVC Isquêmico/metabolismo , Transdução de Sinais , Neuroproteção , Fármacos Neuroprotetores/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Fator de Crescimento Insulin-Like I/metabolismoRESUMO
ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of hematological malignancies. Based on the immunomodulatory capability of CAR-T cells, efforts have turned toward exploring their potential in treating autoimmune diseases. Bibliometric analysis of 210 records from 128 academic journals published by 372 institutions in 40 countries/regions indicates a growing number of publications on CAR-T therapy for autoimmune diseases, covering a range of subtypes such as systemic lupus erythematosus, multiple sclerosis, among others. CAR-T therapy holds promise in mitigating several shortcomings, including the indiscriminate suppression of the immune system by traditional immunosuppressants, and non-sustaining therapeutic levels of monoclonal antibodies due to inherent pharmacokinetic constraints. By persisting and proliferating in vivo , CAR-T cells can offer a tailored and precise therapeutics. This paper reviewed preclinical experiments and clinical trials involving CAR-T and CAR-related therapies in various autoimmune diseases, incorporating innovations well-studied in the field of hematological tumors, aiming to explore a safe and effective therapeutic option for relapsed/refractory autoimmune diseases.