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1.
Arthritis Rheumatol ; 2019 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-31785076

RESUMEN

OBJECTIVE: We previously reported that the co-activation of NF-κB and STAT3 in non-immune cells including synovial fibroblasts enhances the expression of NF-κB target genes, playing a role in chronic inflammation including rheumatoid arthritis (RA). Here we examined the role of NF-κB activation in chondrocytes to understand the pathogenesis of RA. Furthermore, we investigated TMEM147 as a representative NF-κB activator in chondrocytes. METHODS: Clinical samples from RA patients were analyzed by immunohistochemistry. Samples from polydactyly patients served as a control. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several mouse RA models. In vitro experiments including qPCR, RNA interference, immunoprecipitation and confocal microscopy were performed to investigate the mechanism of action of TMEM147 in chondrocytes. RESULTS: Samples from RA patients and from the RA models showed co-activation of NF-κB and STAT3 in chondrocytes (p<0.001). This co-activation induced a synergistic expression of NF-κB targets in vitro (p<0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (p<0.01). TMEM147 was highly expressed in chondrocytes from RA patients and the RA models. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-κB in vitro (p<0.01) and suppressed the cytokine-induced RA in vivo (p<0.01). Mechanistically, TMEM147 molecules acted as a scaffold protein for a NF-κB complex that included breakpoint cluster region and casein kinase 2 to enhance NF-κB activity. CONCLUSION: These results suggest that chondrocytes play a role in the development of RA via TMEM147-mediated NF-κB activation and provide a novel therapeutic strategy for RA.

2.
J Exp Med ; 216(6): 1431-1449, 2019 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-31072819

RESUMEN

Regnase-1 (also known as Zc3h12a or MCPIP-1) is an endoribonuclease involved in mRNA degradation of inflammation-associated genes. Regnase-1 is inactivated in response to external stimuli through post-translational modifications including phosphorylation, yet the precise role of phosphorylation remains unknown. Here, we demonstrate that interleukin (IL)-17 induces phosphorylation of Regnase-1 in an Act1-TBK1/IKKi-dependent manner, especially in nonhematopoietic cells. Phosphorylated Regnase-1 is released from the endoplasmic reticulum (ER) into the cytosol, thereby losing its mRNA degradation function, which leads to expression of IL-17 target genes. By using CRISPR/Cas-9 technology, we generated Regnase-1 mutant mice, in which IL-17-induced Regnase-1 phosphorylation is completely blocked. Mutant mice (Regnase-1AA/AA and Regnase-1ΔCTD/ΔCTD ) were resistant to the IL-17-mediated inflammation caused by T helper 17 (Th17) cells in vivo. Thus, Regnase-1 plays a critical role in the development of IL-17-mediated inflammatory diseases via the Act1-TBK1-IKKi axis, and blockade of Regnase-1 phosphorylation sites may be promising for treatment of Th17-associated diseases.

3.
Sci Rep ; 9(1): 2353, 2019 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-30787395

RESUMEN

We have reported the gateway reflex, which describes specific neural activations that regulate immune cell gateways at specific blood vessels in the central nervous system (CNS). Four types of gateway reflexes exist, all of which induce alterations in endothelial cells at specific vessels of the blood-brain barrier followed by inflammation in the CNS in the presence of CNS-autoreactive T cells. Here we report a new gateway reflex that suppresses the development of retinal inflammation by using an autoreactive T cell-mediated ocular inflammation model. Exposure to photopic light down-regulated the adrenoceptor pathway to attenuate ocular inflammation by suppressing breaching of the blood-retina barrier. Mechanistic analysis showed that exposure to photopic light down-regulates the expression of α1A-adrenoceptor (α1AAR) due to high levels of norepinephrine and epinephrine, subsequently suppressing inflammation. Surgical ablation of the superior cervical ganglion (SCG) did not negate the protective effect of photopic light, suggesting the involvement of retinal noradrenergic neurons rather than sympathetic neurons from the SCG. Blockade of α1AAR signaling under mesopic light recapitulated the protective effect of photopic light. Thus, targeting regional adrenoceptor signaling might represent a novel therapeutic strategy for autoimmune diseases including those that affect organs separated by barriers such as the CNS and eyes.

4.
Neurochem Int ; 130: 104303, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30273641

RESUMEN

Neuroimmunology is a research field that intersects neuroscience and immunology, with the larger aim of gaining significant insights into the pathophysiology of chronic inflammatory diseases such as multiple sclerosis. Conventional studies in this field have so far mainly dealt with immune responses in the nervous system (i.e. neuroinflammation) or systemic immune regulation by the release of glucocorticoids. On the other hand, recently accumulating evidence has indicated bidirectional interactions between specific neural activations and local immune responses. Here we discuss one such local neuroimmune interaction, the gateway reflex. The gateway reflex represents a mechanism that translates specific neural stimulations into local inflammatory outcomes by changing the state of specific blood vessels to allow immune cells to extravasate, thus forming the gateway. Several types of gateway reflex have been identified, and each regulates distinct blood vessels to create gateways for immune cells that induce local inflammation. The gateway reflex represents a novel therapeutic strategy for neuroinflammation and is potentially applicable to other inflammatory diseases in peripheral organs.

5.
J Immunol ; 201(8): 2256-2263, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30201812

RESUMEN

We recently reported that NF-κB-mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the α subunit of casein kinase II (CK2α) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the γ-secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR-CK2α-p65 complex to induce NF-κB activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-κB p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-κB responsive elements and IL-6 promoter. Furthermore, the transcription of NF-κB target genes was not inhibited by a γ-secretase inhibitor, suggesting that Psen1 regulates NF-κB activation in a manner independent of γ-secretase activity. Mechanistically, Psen1 associated with the BCR-CK2α complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-α-induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR-CK2α-p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR-CK2α-p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Quinasa de la Caseína II/metabolismo , Células Endoteliales/fisiología , FN-kappa B/metabolismo , Presenilina-1/genética , Proteínas Proto-Oncogénicas c-bcr/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Regulación de la Expresión Génica , Humanos , Interleucina-6/genética , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , Presenilina-1/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , Proteínas Proto-Oncogénicas c-bcr/genética , ARN Interferente Pequeño/genética , Factor de Transcripción ReIA/metabolismo , Células Tumorales Cultivadas
6.
Cell Rep ; 24(8): 2196-2210.e9, 2018 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-30134179

RESUMEN

We describe a strategy for developing hydrophilic chemical cocktails for tissue delipidation, decoloring, refractive index (RI) matching, and decalcification, based on comprehensive chemical profiling. More than 1,600 chemicals were screened by a high-throughput evaluation system for each chemical process. The chemical profiling revealed important chemical factors: salt-free amine with high octanol/water partition-coefficient (logP) for delipidation, N-alkylimidazole for decoloring, aromatic amide for RI matching, and protonation of phosphate ion for decalcification. The strategic integration of optimal chemical cocktails provided a series of CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) protocols, which efficiently clear mouse organs, mouse body including bone, and even large primate and human tissues. The updated CUBIC protocols are scalable and reproducible, and they enable three-dimensional imaging of the mammalian body and large primate and human tissues. This strategy represents a future paradigm for the rational design of hydrophilic clearing cocktails that can be used for large tissues.


Asunto(s)
Indicadores y Reactivos/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas
7.
Neurochem Int ; 118: 176-184, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29920290

RESUMEN

Multiple sclerosis (MS) is an autoimmune disease in which pathogenic T cells play an important role, and an experimental autoimmune encephalomyelitis (EAE) is used as an animal model of MS. Galectins are ß-galactoside-binding lectins and involved in various physiological and pathological events. Among fifteen members of galectins, galectin-1, -8, and -9 play immunosuppressive roles in MS and EAE; however, the role of galectin-3 (gal-3) is complex and controversial. We examined expression of gal-3 in the spinal cord and nerve roots of EAE mice. No immunohistochemical signals were detected in naïve mice, whereas gal-3 appeared at lower lumbar levels of the spinal cord and nerve roots in EAE mice. In the spinal cord, gal-3-positive cells were activated microglia and/or infiltrating macrophages, which were round in shape and intensified for the lysosomal enzyme, cathepsin D, indicating elevated phagocytic activity. Gal-3-positive cells in the spinal cord were most abundant during the peak symptomatic period. In the recovery period, they disappeared from the spinal parenchyma but remained at moderate levels in the pia mater. Interestingly, gal-3-positive cells selectively appeared in ventral, but not dorsal, nerve roots running through the spinal canal, with expression peaking during the recovery period. In ventral nerve roots, the major cell type expressing gal-3 was a specific population of Schwann cells that surround unmyelinated axons and express the biosynthetic enzyme for l-serine, a potent neurotrophic amino acid. Gal-3 was also induced in Iba1/F4/80-positive macrophages, which engulf damaged myelin and axon debris. Thus, gal-3 is induced in distinct cell types that are engaged in removal of damaged axons and cell debris and axon regeneration and remyelination, suggesting a potential neuroprotective role of gal-3 in EAE mice.


Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Galectina 3/biosíntesis , Galectinas/biosíntesis , Microglía/metabolismo , Células de Schwann/metabolismo , Raíces Nerviosas Espinales/metabolismo , Animales , Técnicas de Cocultivo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Galectina 3/genética , Galectinas/genética , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Células de Schwann/patología , Raíces Nerviosas Espinales/patología
8.
Int Immunol ; 30(7): 281-289, 2018 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-29767741

RESUMEN

The neural regulation of organs can be categorized as systemic or local. Whereas systemic regulation by the hypothalamus-pituitary-adrenal gland-mediated release of steroid hormones has been well studied, the mechanisms for local regulation have only recently emerged. Two types of local neural regulation are known, the gateway reflex and the inflammatory reflex. The gateway reflex describes a mechanism that converts regional neural stimulations into inflammatory outputs by changing the state of specific blood vessels. Molecularly, the enhancement of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity in endothelial cells by neurotransmitters, such as noradrenaline and ATP, induces an enhanced production of pro-inflammatory mediators, including chemokines, which form immune cell gateways at specific vessels. Several types of gateway reflex have been identified, and each regulates distinct organs by creating gateways for autoreactive T cells that induce local inflammation. On the other hand, the inflammatory reflex elicits an anti-inflammatory response through vagal nerves. Here, we summarize recent works on these two local neuro-immune interactions, giving special focus to the gateway reflex.


Asunto(s)
Sistema Nervioso Central/citología , Sistema Nervioso Central/inmunología , Linfocitos/citología , Linfocitos/inmunología , Neuronas/inmunología , Animales , Humanos
9.
Front Immunol ; 8: 1321, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29093711

RESUMEN

The gateway reflex is a new phenomenon that explains how immune cells bypass the blood-brain barrier to infiltrate the central nervous system (CNS) and trigger neuroinflammation. To date, four examples of gateway reflexes have been discovered, each described by the stimulus that evokes the reflex. Gravity, electricity, pain, and stress have all been found to create gateways at specific regions of the CNS. The gateway reflex, the most recently discovered of the four, has also been shown to upset the homeostasis of organs in the periphery through its action on the CNS. These reflexes provide novel therapeutic targets for the control of local neuroinflammation and organ function. Each gateway reflex is activated by different neural activations and induces inflmammation at different regions in the CNS. Therefore, it is theoretically possible to manipulate each independently, providing a novel therapeutic strategy to control local neuroinflammation and peripheral organ homeostasis.

10.
Elife ; 62017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28809157

RESUMEN

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.


Asunto(s)
Encéfalo/fisiología , Encefalomielitis Autoinmune Experimental/complicaciones , Enfermedades Gastrointestinales/fisiopatología , Hipotálamo/patología , Vías Nerviosas/fisiología , Estrés Fisiológico , Animales , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Ratones , Linfocitos T/inmunología
11.
J Exp Med ; 214(5): 1313-1331, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28356392

RESUMEN

Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL-23 contributes to Trypanosoma cruzi-specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23-IL-17 axis during T. cruzi infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of Il23a in innate immune cells. IL-17, but not IFN-γ, was more highly produced by CD4+ T cells from spleens and livers of T. cruzi-infected Batf2-/- mice than by those of wild-type mice. In this context, Batf2-/- mice showed severe multiorgan pathology despite reduced parasite burden. T. cruzi-induced IL-23 production was increased in Batf2-/- innate immune cells. The T. cruzi-induced enhanced Th17 response was abrogated in Batf2-/-Il23a-/- mice. The interaction of BATF2 with c-JUN prevented c-JUN-ATF-2 complex formation, inhibiting Il23a expression. These results demonstrate that IFN-γ-inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during T. cruzi infection.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/fisiología , Enfermedad de Chagas/inmunología , Subunidad p19 de la Interleucina-23/metabolismo , Células Th17/fisiología , Trypanosoma cruzi/inmunología , Animales , Enfermedad de Chagas/patología , Femenino , Inmunidad Innata/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-jun/fisiología , Células Th17/inmunología
13.
Front Microbiol ; 8: 2596, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29403442

RESUMEN

We recently reported that Lactobacillus helveticus SBT2171 (LH2171) inhibited the proliferation and inflammatory cytokine production of primary immune cells in vitro, and alleviated collagen-induced arthritis (CIA) in mice, a model of human rheumatoid arthritis (RA). In this study, we newly investigated whether LH2171 could relieve the severity of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), which is an autoimmune disease, but develop the symptoms by different mechanisms from RA. In MS and EAE, main cause of the disease is the abnormality in CD4+ T cell immunity, whereas in RA and CIA, is that in antibody-mediated immunity. The intraperitoneal administration of LH2171 significantly decreased the incidence and clinical score of EAE in mice. LH2171 also reduced the numbers of pathogenic immune cells, especially Th17 cells, in the spinal cord at the peak stage of disease severity. Interestingly, before the onset of EAE, LH2171 administration remarkably decreased the ratio of Th17 cells to CD4+ T cells in the inguinal lymph nodes (LNs), where pathogenic immune cells are activated to infiltrate the central nervous system, including the spinal cord. Furthermore, the expression of interleukin (IL)-6, an inflammatory cytokine essential for Th17 differentiation, decreased in the LNs of LH2171-administered mice. Moreover, LH2171 significantly inhibited IL-6 production in vitro from both DC2.4 and RAW264.7 cells, model cell lines of antigen-presenting cells. These findings suggest that LH2171 might down-regulate IL-6 production and the subsequent Th17 differentiation and spinal cord infiltration, consequently alleviating EAE symptoms.

14.
Int Immunol ; 29(12): 581-591, 2017 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-29309623

RESUMEN

RNA-binding motif 10 (Rbm10) is an RNA-binding protein that regulates alternative splicing, but its role in inflammation is not well defined. Here, we show that Rbm10 controls appropriate splicing of DNA (cytosine-5)-methyltransferase 3b (Dnmt3b), a DNA methyltransferase, to regulate the activity of NF-κB-responsive promoters and consequently inflammation development. Rbm10 deficiency suppressed NF-κB-mediated responses in vivo and in vitro. Mechanistic analysis showed that Rbm10 deficiency decreased promoter recruitment of NF-κB, with increased DNA methylation of the promoter regions in NF-κB-responsive genes. Consistently, Rbm10 deficiency increased the expression level of Dnmt3b2, which has enzyme activity, while it decreased the splicing isoform Dnmt3b3, which does not. These two isoforms associated with NF-κB efficiently, and overexpression of enzymatically active Dnmt3b2 suppressed the expression of NF-κB targets, indicating that Rbm10-mediated Dnmt3b2 regulation is important for the induction of NF-κB-mediated transcription. Therefore, Rbm10-dependent Dnmt3b regulation is a possible therapeutic target for various inflammatory diseases.


Asunto(s)
Artritis/inmunología , ADN (Citosina-5-)-Metiltransferasas/genética , Inflamación/inmunología , Isoformas de Proteínas/genética , Proteínas de Unión al ARN/metabolismo , Empalme Alternativo/genética , Animales , Artritis/genética , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Inflamación/genética , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/genética , Activación Transcripcional
15.
J Immunol ; 197(8): 3111-3119, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27630163

RESUMEN

The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography-tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR-CK2α complex could be a novel therapeutic target for various inflammatory diseases.


Asunto(s)
Artritis/genética , Quinasa de la Caseína II/metabolismo , Proteínas de Fusión bcr-abl/metabolismo , Cromosoma Filadelfia , Proteínas Proto-Oncogénicas c-bcr/metabolismo , Animales , Artritis Experimental/genética , Línea Celular , Cromatografía Liquida , Proteínas de Fusión bcr-abl/genética , Genes abl/genética , Humanos , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-bcr/genética , ARN Interferente Pequeño/genética , Espectrometría de Masas en Tándem , Factor de Necrosis Tumoral alfa/metabolismo
16.
Int Immunol ; 28(3): 117-26, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26489882

RESUMEN

KDEL receptor 1 (KDELR1) regulates integrated stress responses (ISR) to promote naive T-cell survival in vivo. In a mouse line having nonfunctional KDELR1, T-Red (naive T-cell reduced) mice, polyclonal naive T cells show excessive ISR and eventually undergo apoptosis. However, breeding T-Red mice with TCR-transgenic mice bearing relatively high TCR affinity rescued the T-Red phenotype, implying a link between ISR-induced apoptosis and TCR-mediated signaling. Here, we showed that strong TCR stimulation reduces ISR in naive T cells. In mice lacking functional KDELR1, surviving naive T cells expressed significantly higher levels of CD5, a surrogate marker of TCR self-reactivity. In addition, higher TCR affinity/avidity was confirmed using a tetramer dissociation assay on the surviving naive T cells, suggesting that among the naive T-cell repertoire, those that receive relatively stronger TCR-mediated signals via self-antigens survive enhanced ISR. Consistent with this observation, weak TCR stimulation with altered peptide ligands decreased the survival and proliferation of naive T cells, whereas stimulation with ligands having higher affinity had no such effect. These results suggest a novel role of TCR-mediated signals in the attenuation of ISR in vivo.


Asunto(s)
Estrés del Retículo Endoplásmico/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Péptidos/metabolismo , Transducción de Señal/inmunología , Linfocitos T/fisiología , Animales , Apoptosis/genética , Autoantígenos/inmunología , Antígenos CD5/metabolismo , Supervivencia Celular/genética , Células Cultivadas , Estrés del Retículo Endoplásmico/genética , Homeostasis/genética , Humanos , Memoria Inmunológica , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores de Péptidos/genética , Transducción de Señal/genética
17.
Front Cell Neurosci ; 9: 295, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26300731

RESUMEN

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System (CNS) that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons and axons. Historically, MS has been thought of as a T cell-mediated autoimmune disease of CNS white matter. However, recent studies have identified gray matter lesions in MS patients, suggesting that CNS antigens other than myelin proteins may be involved during the MS disease process. We have recently found that T cells targeting astrocyte-specific antigens can drive unique aspects of inflammatory CNS autoimmunity, including the targeting of gray matter and white matter of the brain and inducing heterogeneous clinical disease courses. In addition to being a target of T cells, astrocytes play a critical role in propagating the inflammatory response within the CNS induced NF-κB signaling. Here, we will discuss the pathophysiology of CNS inflammation mediated by T cell-glial cell interactions and its contributions to CNS autoimmunity.

18.
Elife ; 42015 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-26193120

RESUMEN

Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target.


Asunto(s)
Encefalomielitis Autoinmune Experimental/patología , Esclerosis Múltiple/patología , Dolor , Animales , Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Ratones , Recurrencia , Médula Espinal/patología
19.
Nat Commun ; 6: 7474, 2015 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-26081938

RESUMEN

KDEL receptors are responsible for retrotransporting endoplasmic reticulum (ER) chaperones from the Golgi complex to the ER. Here we describe a role for KDEL receptor 1 (KDELR1) that involves the regulation of integrated stress responses (ISR) in T cells. Designing and using an N-ethyl-N-nitrosourea (ENU)-mutant mouse line, T-Red (naïve T-cell reduced), we show that a point mutation in KDELR1 is responsible for the reduction in the number of naïve T cells in this model owing to an increase in ISR. Mechanistic analysis shows that KDELR1 directly regulates protein phosphatase 1 (PP1), a key phosphatase for ISR in naïve T cells. T-Red KDELR1 does not associate with PP1, resulting in reduced phosphatase activity against eIF2α and subsequent expression of stress responsive genes including the proapoptotic factor Bim. These results demonstrate that KDELR1 regulates naïve T-cell homeostasis by controlling ISR.


Asunto(s)
Proteína Fosfatasa 1/metabolismo , Receptores de Péptidos/metabolismo , Linfocitos T/fisiología , Secuencia de Aminoácidos , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Factor 2 Eucariótico de Iniciación/metabolismo , Femenino , Homeostasis , Memoria Inmunológica , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Fenotipo , Mutación Puntual , Proteínas Proto-Oncogénicas/metabolismo , Receptores de Péptidos/genética , Estrés Fisiológico
20.
Nihon Rinsho ; 73(4): 693-700, 2015 Apr.
Artículo en Japonés | MEDLINE | ID: mdl-25936164

RESUMEN

Inflammation is observed in many diseases and disorders. We discovered a key machinery of inflammation, the inflammation amplifier, which is induced by the simultaneous activation of NFκB and STAT3 followed by the hyper-activation of NFκB in non-immune cells, including endothelial cells and fibroblasts. Since that discovery, we found the Gateway Reflex, which describes regional neural activations that enhance the inflammation amplifier to create a gateway for immune cells to bypass the blood-brain barrier. In addition, we have identified over 1,000 positive regulators and over 500 targets of the inflammation amplifier, which include a significant numbers of human disease-associated genes. In parallel, we performed a comprehensive analysis of human disease samples and found that the inflammation amplifier was activated during the development of chronic inflammation. Thus, we concluded that the inflammation amplifier is associated with various human diseases and disorders, including autoimmune diseases, metabolic syndromes, neurodegenerative diseases, and other inflammatory diseases. We are now attempting drug discovery for inflammatory diseases and disorders based on the inflammation amplifier and Gateway Reflex. In this review, we discuss the Gateway Reflex as an example for the neuro-immune interaction in vivo.


Asunto(s)
Sistema Nervioso Central/inmunología , Inflamación/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Sistema Nervioso Central/metabolismo , Ciclinas/inmunología , Humanos , Reflejo , Transducción de Señal
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