RESUMEN
Interleukin 1ß (IL-1ß) is critical for the in vivo survival, expansion and effector function of IL-17-producing helper T (T(H)17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1ß during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell-intrinsic inflammasome that drives IL-1ß production during T(H)17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1ß, whereas ATP stimulation triggered T cell production of IL-1ß via ASC-NLRP3-dependent caspase-8 activation. IL-1R was detected on T(H)17 cells but not on type 1 helper T (T(H)1) cells, and ATP-treated T(H)17 cells showed enhanced survival compared with ATP-treated T(H)1 cells, suggesting autocrine action of T(H)17-derived IL-1ß. Together these data reveal a critical role for IL-1ß produced by a T(H)17 cell-intrinsic ASC-NLRP3-caspase-8 inflammasome during inflammation of the central nervous system.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Linfocitos T/inmunología , Células Th17/inmunología , Adenosina Trifosfato/farmacología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Adaptadoras de Señalización CARD , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Proteínas Portadoras/metabolismo , Caspasa 8/genética , Caspasa 8/inmunología , Caspasa 8/metabolismo , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Cultivadas , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Citometría de Flujo , Expresión Génica/inmunología , Immunoblotting , Inflamasomas/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-17/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteína con Dominio Pirina 3 de la Familia NLR , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Células Th17/efectos de los fármacos , Células Th17/metabolismoRESUMEN
Microglia-mediated neuroinflammation is involved in various neurological diseases, including ischemic stroke, but the endogenous mechanisms preventing unstrained inflammation is still unclear. The anti-inflammatory role of transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) in macrophages and microglia has previously been identified. However, the endogenous mechanisms that how NR4A1 restricts unstrained inflammation remain elusive. Here, we observed that NR4A1 is up-regulated in the cytoplasm of activated microglia and localizes to processing bodies (P-bodies). In addition, we found that cytoplasmic NR4A1 functions as an RNA-binding protein (RBP) that directly binds and destabilizes Tnf mRNA in an N6-methyladenosine (m6A)-dependent manner. Remarkably, conditional microglial deletion of Nr4a1 elevates Tnf expression and worsens outcomes in a mouse model of ischemic stroke, in which case NR4A1 expression is significantly induced in the cytoplasm of microglia. Thus, our study illustrates a novel mechanism that NR4A1 posttranscriptionally regulates Tnf expression in microglia and determines stroke outcomes.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Ratones , Factores de Transcripción , Microglía , Inflamación , ARN MensajeroRESUMEN
Interleukin 22 (IL-22) has an important role in colorectal tumorigenesis and many colorectal diseases such as inflammatory bowel disease and certain infections. However, the regulation of IL-22 production in the intestinal system is still unclear. Here, we present evidence that butyrophilin-like protein 2 (BTNL2) is required for colorectal IL-22 production, and BTNL2 knockout mice show decreased colonic tumorigenesis and more severe colitis phenotypes than control mice due to defective production of IL-22. Mechanistically, BTNL2 acts on group 3 innate lymphoid cells (ILC3s), CD4+ T cells, and γδ T cells to promote the production of IL-22. Importantly, we find that a monoclonal antibody against BTNL2 attenuates colorectal tumorigenesis in mice and that the mBTNL2-Fc recombinant protein has a therapeutic effect in a dextran sulfate sodium (DSS)-induced colitis model. This study not only identifies a regulatory mechanism of IL-22 production in the colorectal system but also provides a potential therapeutic target for the treatment of human colorectal cancer and inflammatory bowel diseases.
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Colitis , Neoplasias Colorrectales , Humanos , Ratones , Animales , Inmunidad Innata , Linfocitos , Carcinogénesis , Transformación Celular Neoplásica , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales de Enfermedad , Butirofilinas , Interleucina-22RESUMEN
Pyroptosis is a key inflammatory form of cell death participating in the progression of many inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE) and sepsis. Identification of small molecules to inhibit pyroptosis is emerging as an attractive strategy. In this study, we performed a screening based on in silico docking of compounds on the reported Gasdermin D (GSDMD) three-dimensional structure and found C202-2729 demonstrated strong anti-inflammatory effects in both endotoxin shock and EAE mouse models. Oral administration of C202-2729 was capable of attenuating EAE disease severity significantly and has the comparable effects to teriflunomide, the first-line clinical drug of multiple sclerosis. We found C202-2729 remarkably suppressed macrophage and T cell-associated immune inflammation. Mechanistically, C202-2729 neither impact GSDMD cleavage nor the upstream inflammasome activation in mouse immortalized bone marrow-derived macrophages. However, C202-2729 exposure significantly repressed the IL-1ß secretion and cell pyroptosis. We found C202-2729 directly bonds to the N terminus of GSDMD and blocks the migration of the N-terminal GSDMD fragment to cell membrane, restraining the pore-forming and mature IL-1ß release. Collectively, our findings provide a new molecule with the potential for translational application in GSDMD-associated inflammatory diseases.
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Encefalomielitis Autoinmune Experimental , Sepsis , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inflamasomas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Proteínas de Unión a Fosfato/metabolismo , Piroptosis , Sepsis/tratamiento farmacológicoRESUMEN
Opportunistic fungal infections have become one of the leading causes of death among immunocompromised patients, resulting in an estimated 1.5 million deaths each year worldwide. The molecular mechanisms that promote host defense against fungal infections remain elusive. Here, we find that Myosin IF (MYO1F), an unconventional myosin, promotes the expression of genes that are critical for antifungal innate immune signaling and proinflammatory responses. Mechanistically, MYO1F is required for dectin-induced α-tubulin acetylation, acting as an adaptor that recruits both the adaptor AP2A1 and α-tubulin N-acetyltransferase 1 to α-tubulin; in turn, these events control the membrane-to-cytoplasm trafficking of spleen tyrosine kinase and caspase recruitment domain-containing protein 9 Myo1f-deficient mice are more susceptible than their wild-type counterparts to the lethal sequelae of systemic infection with Candida albicans Notably, administration of Sirt2 deacetylase inhibitors, namely AGK2, AK-1, or AK-7, significantly increases the dectin-induced expression of proinflammatory genes in mouse bone marrow-derived macrophages and microglia, thereby protecting mice from both systemic and central nervous system C. albicans infections. AGK2 also promotes proinflammatory gene expression in human peripheral blood mononuclear cells after Dectin stimulation. Taken together, our findings describe a key role for MYO1F in promoting antifungal immunity by regulating the acetylation of α-tubulin and microtubules, and our findings suggest that Sirt2 deacetylase inhibitors may be developed as potential drugs for the treatment of fungal infections.
Asunto(s)
Candida albicans/fisiología , Candidiasis/inmunología , Inmunidad Innata/inmunología , Leucocitos Mononucleares/inmunología , Microtúbulos/inmunología , Miosina Tipo I/metabolismo , Miosina Tipo I/fisiología , Acetilación , Animales , Antifúngicos/farmacología , Candidiasis/tratamiento farmacológico , Candidiasis/metabolismo , Candidiasis/microbiología , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Microtúbulos/microbiología , Miosina Tipo I/genética , Transducción de SeñalRESUMEN
IL-17A plays an essential role in the pathogenesis of many autoimmune diseases, including psoriasis and multiple sclerosis. Act1 is a critical adaptor in the IL-17A signaling pathway. In this study, we report that an anti-sense long noncoding RNA, TRAF3IP2-AS1, regulates Act1 expression and IL-17A signaling by recruiting SRSF10, which downregulates the expression of IRF1, a transcriptional factor of Act1. Interestingly, we found that a psoriasis-susceptible variant of TRAF3IP2-AS1 A4165G (rs13210247) is a gain-of-function mutant. Furthermore, we identified a mouse gene E130307A14-Rik that is homologous to TRAF3IP2-AS1 and has a similar ability to regulate Act1 expression and IL-17A signaling. Importantly, treatment with lentiviruses expressing E130307A14-Rik or SRSF10 yielded therapeutic effects in mouse models of psoriasis and experimental autoimmune encephalomyelitis. These findings suggest that TRAF3IP2-AS1 and/or SRSF10 may represent attractive therapeutic targets in the treatment of IL-17-related autoimmune diseases, such as psoriasis and multiple sclerosis.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Ciclo Celular/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Factor 1 Regulador del Interferón/metabolismo , Interleucina-17/metabolismo , Psoriasis/metabolismo , ARN Largo no Codificante/metabolismo , ARN/metabolismo , Proteínas Represoras/metabolismo , Factores de Empalme Serina-Arginina/metabolismo , Transducción de Señal/genética , Animales , Proteínas de Ciclo Celular/genética , Técnicas de Inactivación de Genes , Células HaCaT , Células HeLa , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , ARN/genética , ARN Largo no Codificante/genética , Proteínas Represoras/genética , Factores de Empalme Serina-Arginina/genética , TransfecciónRESUMEN
IL-37 is a newly identified immune-suppressive factor; however, the function, cellular sources, and mechanism of IL-37 in humoral immunity and Myasthenia gravis (MG) are still unclear. In this study, we found IL-37 were substantially downregulated in the serum and PBMCs of MG patients compared with healthy controls. The lower IL-37 was associated with severer disease (quantitative MG score) and higher follicular Th (Tfh)/Tfh17 and B cell numbers. Flow cytometry analysis revealed that IL-37 was mainly produced by CD4+ T cells without overlapping with Th1, Th17, and Tfh subsets in MG patients. Regulatory IL-37+ T cell rarely expressed Foxp3 and CD25 but produced numerous IL-4. Tfh and B cell expressed high levels of SIGIRR, the receptor of IL-37, in MG patients. Mechanically, IL-37 directly bond to SIGIRR, repressed the proliferation, cytokine production of Tfh and B cells, and the secretion of autoantibody via inhibition of STAT3 signaling in Tfh and B cells.
Asunto(s)
Autoinmunidad/inmunología , Linfocitos B/inmunología , Interleucina-1/inmunología , Miastenia Gravis/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Células Th17/inmunología , Adulto , Autoanticuerpos/inmunología , Células Cultivadas , Femenino , Humanos , Inmunidad Humoral/inmunología , Masculino , Persona de Mediana EdadRESUMEN
Toll-like receptors (TLRs) comprise a group of transmembrane proteins with crucial roles in pathogen recognition, immune responses, and signal transduction. This family represented the first line of immune homeostasis in an evolutionarily conserved manner. Extensive researches in the past two decades had emphasized their structural and functional characteristics under both healthy and pathological conditions. In this review, we summarized the current understanding of TLR signaling in the central nervous system (CNS), which had been viewed as a previously "immune-privileged" but now "immune-specialized" area, with major implications for further investigation of pathological nature as well as potential therapeutic manipulation of TLR signaling in various neurological disorders.
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Transducción de Señal , Receptores Toll-Like , Encéfalo/metabolismo , Sistema Nervioso Central/metabolismo , Humanos , Inmunidad Innata , Receptores Toll-Like/metabolismoRESUMEN
Myasthenia gravis (MG) is a chronic humoral immunity-mediated autoimmune disorder of the neuromuscular junction characterized by muscle weakness. Follicular helper T (Tfh) cells may be the key Th cell subset that promotes MG development, as their major function is helping B cell activation and Ab production. Aberrance of thymus-derived Tfh cells might be implicated in autoimmune diseases including MG; just how circulating Tfh cells, especially those from patients with a normal thymus, contribute to MG pathogenesis remains to be uncovered. In this article, we characterize a population of circulating CD4(+)CXCR5(+)PD-1(+) Tfh cells in ocular and generalized MG patients without thymic abnormalities and demonstrate that the circulating Tfh cells are significantly enriched in generalized MG patients but not in ocular MG patients compared with healthy subjects, whereas a proportion of follicular regulatory T cells decreased in MG patients. In addition, the frequency of plasma cells and B cells was higher and the serum levels of IL-6/IL-21 were also elevated in these MG patients. The activated Tfh1 and Tfh17 in Tfh cells are the major source for IL-21 production in MG patients. A strong correlation between Tfh cells and the plasma cell frequency and anti-acetylcholine receptor Ab titers was evident in generalized MG patients. In particular, we found that Tfh cells derived from MG patients promoted B cells to produce Abs in an IL-21 signaling-dependent manner. Collectively, our results suggest that circulating Tfh cells may act on autoreactive B cells and thus contribute to the development of MG in patients without thymic abnormalities.
Asunto(s)
Linfocitos B/inmunología , Miastenia Gravis/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/patología , Estudios ProspectivosRESUMEN
Glatiramer acetate (GA) is one of the first-line disease-modifying medications that have been approved for the treatment of multiple sclerosis via immune modulatory mechanisms. However, it remains unclear whether the immunomodulation effect of GA is central nervous system (CNS) antigen specific. Here, we explored the mechanism of action of GA by subcutaneously injecting GA in experimental autoimmune neuritis (EAN) rats, an animal model for Guillain-Barré syndrome (GBS). Clinical, electrophysiological and histological findings showed that neurological deficits, demyelination and axonal injury of sciatic nerves were all significantly attenuated in Lewis rats when GA was administered before immunization with peripheral nervous system antigen P0. Our results further demonstrated that GA treatment inhibited either P0 or myelin basic protein (MBP) (CNS antigen)-stimulated auto-immune T-cell proliferation in vitro. GA administrated at 10 days after induction of EAN when neurological sign became apparent also ameliorated the severity of disease, inhibited T-cell response to P0 and MBP and induced shift of proinflammatory and immune modulatory cytokines. Collectively, our findings suggested that GA attenuated neurological deficits in EAN rats and that the immune modulatory mechanisms of GA were not CNS antigen specific.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Síndrome de Guillain-Barré/tratamiento farmacológico , Inmunosupresores/farmacología , Neuritis Autoinmune Experimental/tratamiento farmacológico , Péptidos/farmacología , Linfocitos T/inmunología , Animales , Acetato de Glatiramer , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/patología , Neuritis Autoinmune Experimental/inmunología , Neuritis Autoinmune Experimental/patología , Ratas , Ratas Endogámicas Lew , Linfocitos T/patologíaRESUMEN
Microglia and oligodendrocyte precursor cells (OPCs) are critical glia subsets in the central nervous system (CNS) and are actively engaged in a body of diseases, such as stroke, Alzheimer's disease, multiple sclerosis, etc. Microglia and OPC serve as compelling tools for the study of CNS diseases as well as the repair and damage of myelin sheath in vitro. In this protocol, we summarized a method which is capable of using the same batch of new-born mice to isolate and culture microglia and OPCs. It integrates the characteristics of practicality, convenience, and efficiency, providing a convenient, easy, and reliable technique for research.
Asunto(s)
Microglía , Células Precursoras de Oligodendrocitos , Ratones , Animales , Diferenciación Celular/fisiología , Vaina de Mielina , Sistema Nervioso Central , OligodendroglíaRESUMEN
T cells are a heterogeneous group of cells that can be classified into different subtypes according to different classification methods. The body's immune system has a highly complex and effective regulatory network that allows for the relative stability of immune system function. Maintaining proper T cell homeostasis is essential for promoting protective immunity and limiting autoimmunity and tumor formation. Among the T cell family members, more and more T cell subsets have gradually been characterized. In this chapter, we summarize the functions of some key T cell subsets and their impact on immune homeostasis.
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Neoplasias , Linfocitos T Reguladores , Humanos , Subgrupos de Linfocitos T , Autoinmunidad , HomeostasisRESUMEN
AIMS: Pyroptosis is a unique pro-inflammatory form of programmed cell death which plays a critical role in promoting the pathogenesis of multiple inflammatory and autoimmune diseases. However, the current drug that is capable of inhibition pyroptosis has not been translated successfully in the clinic, suggesting a requirement for drug screening in depth. METHODS: We screened more than 20,000 small molecules and found D359-0396 demonstrates a potent anti-pyroptosis and anti-inflammation effect in both mouse and human macrophage. In vivo, EAE (a mouse model of MS) and septic shock mouse model was used to investigate the protective effect of D359-0396. In vitro experiments we used LPS plus ATP/nigericin/MSU to induce pyroptosis in both mouse and human macrophage, and finally the anti-pyroptosis function of D359-0396 was assessed. RESULTS: Our findings show that D359-0396 is well-tolerated without remarkable disruption of homeostasis. Mechanistically, while D359-0396 is capable of inhibiting pyroptosis and IL-1ß release in macrophages, this process depends on the NLRP3-Casp1-GSDMD pathway rather than NF-κB, AIM2 or NLRC4 inflammasome signaling. Consistently, D359-0396 significantly suppresses the oligomerization of NLRP3, ASC, and the cleavage of GSDMD. In vivo, D359-0396 not only ameliorates the severity of EAE (a mouse model of MS), but also exhibits a better therapeutic effect than teriflunomide, the first-line drug of MS. Similarly, D359-0396 treatment also significantly protects mice from septic shock. CONCLUSION: Our study identified D359-0396 as a novel small-molecule with potential application in NLRP3-associated diseases.
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Inflamasomas , Choque Séptico , Humanos , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Choque Séptico/inducido químicamente , Choque Séptico/tratamiento farmacológico , FN-kappa B/metabolismo , Transducción de Señal , Modelos Animales de EnfermedadRESUMEN
In this paper, we study the effect of microbial fermentation on the nutrient composition and flavor of sweet potato slurry, different strains of Aspergillus niger, Saccharomyces cerevisiae, Lactobacillus plantarum, Bacillus coagulans, Bacillus subtilis, Lactobacillus acidophilus, and Bifidobacterium brevis were employed to ferment sweet potato slurry. After 48 h of fermentation with different strains (10% inoculation amount), we compared the effects of several strains on the nutritional and functional constituents (protein, soluble dietary fiber, organic acid, soluble sugar, total polyphenol, free amino acid, and sensory characteristics). The results demonstrated that the total sugar level of sweet potato slurry fell significantly after fermentation by various strains, indicating that these strains can utilize the nutritious components of sweet potato slurry for fermentation. The slurry's total protein and phenol concentrations increased significantly, and many strains demonstrated excellent fermentation performance. The pH of the slurry dropped from 6.78 to 3.28 to 5.95 after fermentation. The fermentation broth contained 17 free amino acids, and the change in free amino acid content is closely correlated with the flavor of the sweet potato fermentation slurry. The gas chromatography-mass spectrometry results reveal that microbial fermentation can effectively increase the kinds and concentration of flavor components in sweet potato slurry, enhancing its flavor and flavor profile. The results demonstrated that Aspergillus niger fermentation of sweet potato slurry might greatly enhance protein and total phenolic content, which is crucial in enhancing nutrition. However, Bacillus coagulans fermentation can enhance the concentration of free amino acids in sweet potato slurry by 64.83%, with a significant rise in fresh and sweet amino acids. After fermentation by Bacillus coagulans, the concentration of lactic acid and volatile flavor substances also achieved its highest level, which can considerably enhance its flavor. The above results showed that Aspergillus niger and Bacillus coagulans could be the ideal strains for sweet potato slurry fermentation.
RESUMEN
Fungal infection or proliferation in our body is capable of initiation of strong inflammation and immune responses that result in different consequences, including infection-trigged organ injury and inflammation-related remote organ dysfunction. Fungi associated infectious diseases have been well recognized in the clinic. However, whether fungi play an important role in non-infectious central nervous system disease is still to be elucidated. Recently, a growing amount of evidence point to a non-negligible role of peripheral fungus in triggering unique inflammation, immune response, and exacerbation of a range of non-infectious CNS disorders, including Multiple sclerosis, Neuromyelitis optica, Parkinson's disease, Alzheimer's disease, and Amyotrophic lateral sclerosis et al. In this review, we summarized the recent advances in recognizing patterns and inflammatory signaling of fungi in different subsets of immune cells, with a specific focus on its function in CNS autoimmune and neurodegeneration diseases. In conclusion, the fungus is capable of triggering unique inflammation by multiple mechanisms in the progression of a body of CNS non-infectious diseases, suggesting it serves as a key factor and critical novel target for the development of potential therapeutic strategies.
Asunto(s)
Enfermedades del Sistema Nervioso Central , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Sistema Nervioso Central , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Hongos , InflamaciónRESUMEN
Gasdermin D (GSDMD) serves as a key executor to trigger pyroptosis and is emerging as an attractive checkpoint in host defense, inflammatory, autoimmune diseases, and many other systemic diseases. Although canonical and non-canonical inflammasome-mediated classic GSDMD cleavage, GSDMD-NT migration to cell membrane, GSDMD-NT oligomerization, and pore forming have been well recognized, a few unique features of GSDMD in specific condition beyond its classic function, including non-lytic function of GSDMD, the modification and regulating mechanism of GSDMD signaling have also come to great attention and played a crucial role in biological processes and diseases. In the current review, we emphasized the GSDMD protein expression, stabilization, modification, activation, pore formation, and repair during pyroptosis, especially the regulation and modification of GSDMD signaling, such as GSDMD complex in polyubiquitination and non-pyroptosis release of IL-1ß, ADP-riboxanation, NINJ1 in pore forming, GSDMD binding protein TRIM21, GSDMD succination, and Regulator-Rag-mTOR-ROS regulation of GSDMD. We also discussed the novel therapeutic strategies of targeting GSDMD and summarized recently identified inhibitors with great prospect.
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Fenómenos Biológicos , Péptidos y Proteínas de Señalización Intracelular , Inflamasomas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Unión a Fosfato/metabolismo , PiroptosisRESUMEN
The C-type lectin receptor Mincle is known for its important role in innate immune cells in recognizing pathogen and damage associated molecular patterns. Here we report a T cell-intrinsic role for Mincle in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Genomic deletion of Mincle in T cells impairs TH17, but not TH1 cell-mediated EAE, in alignment with significantly higher expression of Mincle in TH17 cells than in TH1 cells. Mechanistically, dying cells release ß-glucosylceramide during inflammation, which serves as natural ligand for Mincle. Ligand engagement induces activation of the ASC-NLRP3 inflammasome, which leads to Caspase8-dependent IL-1ß production and consequentially TH17 cell proliferation via an autocrine regulatory loop. Chemical inhibition of ß-glucosylceramide synthesis greatly reduces inflammatory CD4+ T cells in the central nervous system and inhibits EAE progression in mice. Taken together, this study indicates that sensing of danger signals by Mincle on TH17 cells plays a critical role in promoting CNS inflammation.
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Encefalomielitis Autoinmune Experimental , Células Th17 , Animales , Sistema Nervioso Central/metabolismo , Glucosilceramidas/metabolismo , Inflamación/metabolismo , Ligandos , RatonesRESUMEN
Therapeutic blockade of the immune checkpoint proteins programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has transformed cancer treatment. However, the overall response rate to these treatments is low, suggesting that immune checkpoint activation is not the only mechanism leading to dysfunctional anti-tumour immunity. Here we show that butyrophilin-like protein 2 (BTNL2) is a potent suppressor of the anti-tumour immune response. Antibody-mediated blockade of BTNL2 attenuates tumour progression in multiple in vivo murine tumour models, resulting in prolonged survival of tumour-bearing mice. Mechanistically, BTNL2 interacts with local γδ T cell populations to promote IL-17A production in the tumour microenvironment. Inhibition of BTNL2 reduces the number of tumour-infiltrating IL-17A-producing γδ T cells and myeloid-derived suppressor cells, while facilitating cytotoxic CD8+ T cell accumulation. Furthermore, we find high BTNL2 expression in several human tumour samples from highly prevalent cancer types, which negatively correlates with overall patient survival. Thus, our results suggest that BTNL2 is a negative regulator of anti-tumour immunity and a potential target for cancer immunotherapy.
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Butirofilinas/genética , Butirofilinas/metabolismo , Interleucina-17/metabolismo , Linfocitos T/metabolismo , Escape del Tumor/fisiología , Animales , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4 , Femenino , Expresión Génica , Células HEK293 , Humanos , Inmunoterapia , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias , Linfocitos T Citotóxicos/inmunología , Microambiente TumoralRESUMEN
Vascular smooth muscle cells (VSMCs) have been widely recognized as key players in regulating blood-brain barrier (BBB) function, and their roles are unclear in ischemic stroke. Myosin phosphatase target subunit 1 (MYPT1) is essential for VSMC contraction and maintaining healthy vasculature. We generated VSMC-specific MYPT1 knockout (MYPT1SMKO) mice and cultured VSMCs infected with Lv-shMYPT1 to explore phenotypic switching of VSMCs and the accompanied impacts on BBB integrity. We found that MYPT1 deficiency induced phenotypic switching of synthetic VSMCs, which aggravated BBB disruption. Proteomic analysis identified evolutionarily conserved signaling intermediates in Toll pathways (ECSIT) as a downstream molecule that promotes activation of synthetic VSMCs and contributed to IL-6 expression. Knocking down ECSIT rescued phenotypic switching of VSMCs and BBB disruption. Additionally, inhibition of IL-6 decreased BBB permeability. These findings reveal that MYPT1 deficiency activated phenotypic switching of synthetic VSMCs and induced BBB disruption through ECSIT-IL-6 signaling after ischemic stroke.
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Background: Stem cell transplantation is emerging as a potential therapeutic strategy in several autoimmune diseases. However, the safety and feasibility of long-term combined intravenous (IV) and intrathecal (IT) administration of hUC-MSCs in relapse remitting multiple sclerosis (RRMS) and neuromyelitis optica (NMO) is largely unknown. Objectives: In this study, we followed up the long-term safety and feasibility of combined IV and IT human umbilical cord mesenchymal stem cells (hUC-MSCs) transplantation in patients with RRMS and NMO. Methods: Five NMO patients and 5 RRMS patients were treated intravenously (4 times) and intrathecally (3 times) over a 21-day period with low-dose allogeneic umbilical cord blood-derived MSCs. All of the patients were monitored regularly by an investigator in a blinded manner to access the Expanded Disability Status Scale, MRI characteristics, and adverse events every 3 months within 12 months and once every year thereafter for 10 years after transplantation. Results: During the long-term follow-up, our data suggested that combined IV and IT administration of hUC-MSCs transplantation is safe and feasible. None of the intolerant adverse events, such as tumor formation and peripheral organ/tissue disorders, were observed throughout the 10-year follow-up. Conclusions: These data suggest that combined intravenous and intrathecal low-dose hUC-MSCs transplantation is safe and feasible in RRMS and NMO patients in the long term. The conclusion requires confirmation by future clinical trials in a larger cohort.