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Demyelination and axonal injury in chronic-progressive Multiple Sclerosis (MS) are presumed to be driven by a neurotoxic bystander effect of meningeal-based myeloid infiltrates. There is an unmet clinical need to attenuate disease progression in such forms of CNS-compartmentalized MS. The failure of systemic immune suppressive treatments has highlighted the need for neuroprotective and repair-inducing strategies. Here, we examined whether direct targeting of CNS myeloid cells and modulating their toxicity may prevent irreversible tissue injury in chronic immune-mediated demyelinating disease. To that end, we utilized the experimental autoimmune encephalomyelitis (EAE) model in Biozzi mice, a clinically relevant MS model. We continuously delivered intracerebroventricularly (ICV) a retinoic acid receptor alpha agonist (RARα), as a potent regulator of myeloid cells, in the chronic phase of EAE. We assessed disease severity and performed pathological evaluations, functional analyses of immune cells, and single-cell RNA sequencing on isolated spinal CD11bâ¯+â¯cells. Although initiating treatment in the chronic phase of the disease, the RARα agonist successfully improved clinical outcomes and prevented axonal loss. ICV RARα agonist treatment inhibited pro-inflammatory pathways and shifted CNS myeloid cells toward neuroprotective phenotypes without affecting peripheral infiltrating myeloid cell phenotypes, or peripheral immunity. The treatment regulated cell-death pathways across multiple myeloid cell populations and suppressed apoptosis, resulting in paradoxically marked increased neuroinflammatory infiltrates, consisting mainly of microglia and CNS / border-associated macrophages. This work establishes the notion of bystander neurotoxicity by CNS immune infiltrates in chronic demyelinating disease. Furthermore, it shows that targeting compartmentalized neuroinflammation by selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury, and may serve as a novel disease-modifying approach.
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Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide. Emerging research has challenged the conventional notion of a direct correlation between amyloid deposition and neurodegeneration in AD. Recent studies have suggested that amyloid and Tau deposition act as a central nervous system (CNS) innate immune driver event, inducing chronic microglial activation that increases the susceptibility of the AD brain to the neurotoxicity of infectious insults. Although modifiable risk factors account for up to 50% of AD risk, the mechanisms by which they interact with the core process of misfolded protein deposition and neuroinflammation in AD are unclear and require further investigation. This update introduces a novel perspective, suggesting that modifiable risk factors act as external insults that, akin to infectious agents, cause neurodegeneration by inducing recurrent acute neurotoxic microglial activation. This pathological damage occurs in AD pathology-primed regions, creating a "hit and run" mechanism that leaves no discernible pathological trace of the external insult. This model, highlighting microglia as a pivotal player in risk factor-mediated neurodegeneration, offers a new point of view on the complex associations of modifiable risk factors and proteinopathy in AD pathogenesis, which may act in parallel to the thoroughly studied amyloid-driven Tau pathology, and strengthens the therapeutic rationale of combining immune modulation with tight control of risk factor-driven insults.
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Doença de Alzheimer , Síndromes Neurotóxicas , Humanos , Doença de Alzheimer/metabolismo , Sistema Nervoso Central/metabolismo , Microglia/metabolismo , Encéfalo/metabolismo , Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Síndromes Neurotóxicas/patologia , Peptídeos beta-Amiloides/metabolismoRESUMO
The impact of high-intensity interval training (HIIT) on the central nervous system (CNS) in autoimmune neuroinflammation is not known. The aim of this study was to determine the direct effects of HIIT on the CNS and development of experimental autoimmune encephalomyelitis (EAE). Healthy mice were subjected to HIIT by treadmill running and the proteolipid protein (PLP) transfer EAE model was utilized. To examine neuroprotection, PLP-reactive lymph-node cells (LNCs) were transferred to HIIT and sedentary (SED) mice. To examine immunomodulation, PLP-reactive LNCs from HIIT and SED donor mice were transferred to naïve recipients and analyzed in vitro. HIIT in recipient mice did not affect the development of EAE following exposure to PLP-reactive LNCs. HIIT mice exhibited enhanced migration of systemic autoimmune cells into the CNS and increased demyelination. In contrast, EAE severity in recipient mice injected with PLP-reactive LNCs from HIIT donor mice was significantly diminished. The latter positive effect was associated with decreased migration of autoimmune cells into the CNS and inhibition of very late antigen (VLA)-4 expression in LNCs. Thus, the beneficial effect of HIIT on EAE development is attributed solely to systemic immunomodulatory effects, likely because of systemic inhibition of autoreactive cell migration and reduced VLA-4 integrin expression.
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Encefalomielite Autoimune Experimental , Encefalomielite , Treinamento Intervalado de Alta Intensidade , Camundongos , Animais , Sistema Nervoso Central/metabolismo , Imunomodulação , Proteína Proteolipídica de MielinaAssuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/prevenção & controle , Vacina BCG , Imunização , VacinaçãoRESUMO
Remyelination failure is considered a major obstacle in treating chronic-progressive multiple sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need for a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models. We examined PD0325901 effects in the chronically inflamed central nervous system. Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive experimental autoimmune encephalomyelitis with PD0325901 showed no clinical improvement in comparison to the control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC. Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro-myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.
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BACKGROUND: Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients. METHODS: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 106 AstroRx® cells and 5 patients with 250 × 106 cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period). RESULTS: A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 106 AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from - 0.88/month pre-treatment to - 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 106 AstroRx® arm, the ALSFRS-R slope decreased from - 1.43/month to - 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study. CONCLUSIONS: Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 106 or 250 × 106 cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months. TRIAL REGISTRATION: NCT03482050.
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Esclerose Lateral Amiotrófica , Transplante de Células-Tronco Mesenquimais , Humanos , Esclerose Lateral Amiotrófica/terapia , Astrócitos , Injeções Espinhais , Transplante de Células-Tronco Mesenquimais/métodosRESUMO
BACKGROUND: The mechanisms by which exercise training (ET) elicits beneficial effects on the systemic immune system and the central nervous system (CNS) in autoimmune neuroinflammation are not fully understood. OBJECTIVES: To investigate (1) the systemic effects of high-intensity continuous training (HICT) on the migratory potential of autoimmune cells; (2) the direct effects of HICT on blood-brain-barrier (BBB) properties. METHODS: Healthy mice were subjected to high-intensity continuous training (HICT) by treadmill running. The proteolipid protein (PLP) transfer EAE model was utilized to examine the immunomodulatory effects of training, where PLP-reactive lymph-node cells (LNCs) from HICT and sedentary donor mice were analyzed in vitro and transferred to naïve recipients that developed EAE. To examine neuroprotection, encephalitogenic LNCs from donor mice were transferred into HICT or sedentary recipient mice and the BBB was analyzed. RESULTS: Transfer of PLP-reactive LNCs obtained from HICT donor mice attenuated EAE severity and inflammation in recipient mice. HICT markedly inhibited very late antigen (VLA)-4 and lymphocyte function-associated antigen (LFA)-1 expression in LNCs. Transfer of encephalitogenic LNCs into HICT recipients resulted in milder EAE and attenuated CNS inflammation. HICT reduced BBB permeability and the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in CNS blood vessels. INTERPRETATION: HICT attenuates EAE development by both immunomodulatory and neuroprotective effects. The reduction in destructive CNS inflammation in EAE is attributed to systemic inhibition of autoreactive cell migratory potential, as well as reduction in BBB permeability, which are associated with reduced VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions.
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Encefalite , Encefalomielite Autoimune Experimental , Encefalomielite , Animais , Camundongos , Encefalomielite Autoimune Experimental/terapia , Encéfalo/metabolismo , Barreira Hematoencefálica , Encefalite/metabolismo , Inflamação/metabolismoRESUMO
BACKGROUND: The Amyloid theory of Alzheimer's disease (AD) suggests that the deposition of Amyloid ß (Aß) in the brain triggers a chain of events, involving the deposition of phosphorylated Tau and other misfolded proteins, leading to neurodegeneration via neuroinflammation, oxidative stress, and neurovascular factors. The infectious theory linked various infectious agents with the development of AD, raising the possibility that they serve as etiological causes of the disease. Are these theories mutually exclusive, or do they coincide? MAIN BODY: In this review, we will discuss how the two theories converge. We present a model by which (1) the systemic infectious burden accelerates the development of AD brain pathology via bacterial Amyloids and other pathogen-associated molecular patterns (PAMPs), and (2) the developing AD brain pathology increases its susceptibility to the neurotoxicity of infectious agents -derived PAMPs, which drive neurodegeneration via activated microglia. CONCLUSIONS: The reciprocal effects of amyloid deposition and systemic infectious burden may lead to a vicious cycle fueling Alzheimer's disease pathogenesis.
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Doença de Alzheimer , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Humanos , Moléculas com Motivos Associados a Patógenos/metabolismoRESUMO
Background: Meningitis and meningoencephalitis (MME) are potential medical emergencies. Mandatory reporting of all MME cases in the Israel Defense Force (IDF) allows accurate characterization of MME incidence and course. In the present study, we described the epidemiology of MME in soldiers. Methods: Medical charts of 860,000 combat and non-combat soldiers serving during the years 2004-2015, accounting for 2,256,060 patient years, were retrospectively evaluated. The diagnosis of MME was based on signs of meningeal irritation and a count of > 5 white blood cells (WBC) in the cerebrospinal fluid (CSF). Data on the diagnosis of bacterial or aseptic MME, significant sequelae, and associated mortality were collected. Results: Approximately 273 cases of MME were diagnosed. Overall, MME incidence was 12.1/100,000 patient-years. Bacterial and viral pathogens were identified in 31/273 (11.4%) and 52/273 (19%) cases, respectively. Combat soldiers had higher incidence of bacterial meningitis [14/40 (35%) vs. 31/212 (14.6%); p = 0.002] and meningoencephalitis [13/40 (32.5%) vs. 33/212 (15.6%); p = 0.023] compared to non-combat soldiers. Their clinical presentation was more severe, including confusion [10/40 (25%) vs. 22/212 (10.4%); p = 0.018], focal neurological deficits [12/40 (30%) vs. 11/212 (5.2%); p < 0.0001], and status epilepticus [3/40 (7.5%) vs. 0/212 (0.0%); p < 0.01]. Mortality among combat soldiers was higher [5/40 (15%) vs. 1/212 (0.5%); p < 0.001]. N. meningitidis was the most frequently isolated bacteria, despite universal preventative vaccination. Conclusion: The incidence of bacterial MME in the IDF is higher than in the civilian population. Combat soldiers present with higher incidence of meningoencephalitis and bacterial meningitis.
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Current literature lacks structured methodologies for analyzing medical technologies' impact from the patient-centered care perspective. This study introduces, applies and validates 'Patient-Centered Care Impact Analysis' (PCIA) as a method for identifying patient-centered care associated demands and expectations for a particular technology and assessing its compliance with these demands. PCIA involves five stages: (1) demand identification, (2) ranking demands' impact magnitude, (3) scoring demand compliance (DC), (4) demand priority (DP) assignment based on impact magnitude and compliance, (5) generating a summative impact priority number (IPN). PCIA was performed as a comparative assessment of two central nervous system (CNS) drug-delivery platforms; SipNose, a novel noninvasive Direct-Nose-to-Brain (DNTB), vs. the standard-of-care invasive intrathecal/intracerebroventricular injection (Invasive I/I). Study participants included a ranking team (RT) without experience with the SipNose technology that based their scoring on experimental data; and a validation team (VT) experienced with the SipNose platform. All had experience with, or knowledge of, InvasiveI/I. Demand identification and impact magnitude were performed by one content and one assessment expert. Each participant assessed each technology's DC. DP scores, IPN's and IPN DNTB:InvasiveI/I ratios were generated for each technology, for each team, based on DC and summative DP scores, respectively. Both teams assigned DNTB higher DC scores, resulting in higher DNTB DP, IPN scores and DNTB:InvasiveI/I IPN ratios. Lack of difference between team assessments of DP and IPN ratio validate PCIA as an assessment tool capable of predicting patient-centered clinical care quality for a new technology. The significant differences between the platforms highlight SipNose's patient-care centered advantages as an effective CNS drug-delivery platform.
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Encéfalo , Sistemas de Liberação de Medicamentos , Fármacos do Sistema Nervoso Central , Humanos , Assistência Centrada no PacienteRESUMO
The failure of brain microglia to clear excess amyloid ß (Aß) is considered a leading cause of the progression of Alzheimer's disease pathology. Resident brain neural precursor cells (NPCs) possess immune-modulatory and neuro-protective properties, which are thought to maintain brain homeostasis. We have recently showed that resident mouse brain NPCs exhibit an acquired decline in their trophic properties in the Alzheimer's disease brain environment. Therefore, we hypothesized that functional NPCs may support microglial phagocytic activity, and that NPCs derived from the adult AD mouse brain may fail to support the clearance of Aß by microglia. We first identified in the AD brain, in vivo and ex vivo, a subpopulation of microglia that express high Aß phagocytic activity. Time-lapse microscopy showed that co-culturing newborn NPCs with microglia induced a significant increase in the fraction of microglia with high Aß phagocytic activity. Freshly isolated NPCs from adult wild type, but not AD, mouse brain, induced an increase in the fraction of microglia with high Aß phagocytic activity. Finally, we showed that NPCs also possess the ability to promote Aß degradation within the microglia with high Aß phagocytic activity. Thus, resident brain NPCs support microglial function to clear Aß, but NPCs derived from the AD environment fail to do so. We suggest that the failure of AD brain NPCs to support Aß clearance from the brain by microglia may accelerate disease pathology.
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Doença de Alzheimer , Células-Tronco Neurais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Células-Tronco Neurais/metabolismoRESUMO
BACKGROUND: Neurodegeneration is considered the consequence of misfolded proteins' deposition. Little is known about external environmental effects on the neurodegenerative process. Infectious agent-derived pathogen-associated molecular patterns (PAMPs) activate microglia, key players in neurodegenerative diseases. We hypothesized that systemic microbial pathogens may accelerate neurodegeneration in Alzheimer's disease (AD) and that microglia play a central role in this process. METHODS: We examined the effect of an infectious environment and of microbial Toll-like receptor (TLR) agonists on cortical neuronal loss and on microglial phenotype in wild type versus 5xFAD transgenic mice, carrying mutated genes associated with familial AD. RESULTS: We examined the effect of a naturally bred environment on the neurodegenerative process. Earlier and accelerated cortical neuron loss occurred in 5xFAD mice housed in a natural ("dirty") environment than in a specific-pathogen-free (SPF) environment, without increasing the burden of Amyloid deposits and microgliosis. Neuronal loss occurred in a microglia-rich cortical region but not in microglia-poor CA regions of the hippocampus. Environmental exposure had no effect on cortical neuron density in wild-type mice. To model the neurodegenerative process caused by the natural infectious environment, we injected systemically the bacterial endotoxin lipopolysaccharide (LPS), a TLR4 agonist PAMP. LPS caused cortical neuronal death in 5xFAD, but not wt mice. We used the selective retinoic acid receptor α agonist Am580 to regulate microglial activation. In primary microglia isolated from 5xFAD mice, Am580 markedly attenuated TLR agonists-induced iNOS expression, without canceling their basic immune response. Intracerebroventricular delivery of Am580 in 5xFAD mice reduced significantly the fraction of (neurotoxic) iNOS + microglia and increased the fraction of (neuroprotective) TREM2 + microglia. Furthermore, intracerebroventricular delivery of Am580 prevented neurodegeneration induced by microbial TLR agonists. CONCLUSIONS: Exposure to systemic infections causes neurodegeneration in brain regions displaying amyloid pathology and high local microglia density. AD brains exhibit increased susceptibility to microbial PAMPs' neurotoxicity, which accelerates neuronal death. Microglial modulation protects the brain from microbial TLR agonist PAMP-induced neurodegeneration.
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Doença de Alzheimer/patologia , Encéfalo/patologia , Microglia/patologia , Degeneração Neural/patologia , Neurônios/patologia , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fagocitose/efeitos dos fármacosRESUMO
Physical exercise (PE) impacts various autoimmune diseases. Accordingly, clinical trials demonstrated the safety of PE in multiple sclerosis (MS) patients and indicated beneficial outcomes. There is also an increasing body of research on the beneficial effects of exercise on experimental autoimmune encephalomyelitis (EAE), the animal model of MS, and various mechanisms underlying these effects were suggested. However, despite the documented favorable impact of PE on our health, we still lack a thorough understanding of its effects on autoimmune neuroinflammation and specific guidelines of PE therapy for MS patients are lacking. To that end, current findings on the impact of PE on autoimmune neuroinflammation, both in human MS and animal models are reviewed. The concept of personalized PE therapy for autoimmune neuroinflammation is discussed, and future research for providing biological rationale for clinical trials to pave the road for precise PE therapy in MS patients is described.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/terapia , Exercício Físico , Humanos , Esclerose Múltipla/terapia , Doenças Neuroinflamatórias , Assistência ao PacienteRESUMO
Neural stem/precursor cells (NPC) exhibit powerful immune-modulatory properties. Attenuation of neuroinflammation by intra-cerebroventricular transplantation of NPC, protects from immune-mediated demyelination and axonal injury. The immune modulatory properties of NPC are mediated by a non-species-specific, multiple bystander effect, mediated by both direct cell-cell contact, and by soluble factor(s). CD200 is a cell-surface molecule, with important roles in regulating diverse immune responses, and shown also to limit neuroinflammatory processes. We hypothesized that CD200 may play a role in mediating immune-modulatory effects of NPC. We used wild type and CD200-deficient NPC to examine the role of CD200 in mediating two vital aspects of NPC -immune modulatory properties: (1) Attenuation of autoimmune neuroinflammation; and (2) Suppression of immune rejection response towards transplanted allogeneic NPC from the host CNS. We found that CD200 is dispensable for attenuating acute experimental autoimmune neuroinflammation, but is required for protecting transplanted allogeneic NPC from immune rejection by the host tissue. CD200 deficient NPC showed similar growth, differentiation and survival properties as wild type NPC. CD200-deficient NPC attenuated efficiently T cell activation and proliferation, but exhibited reduced ability to inhibit macrophages. We conclude that CD200 plays a partial role in mediating the immune-modulatory properties of NPC. The differential effect on T cells versus macrophages may underlie the observed discrepancy in their function in vivo.
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Células-Tronco Neurais , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Diferenciação Celular , Imunidade , Macrófagos , CamundongosRESUMO
Brain stimulation by electroconvulsive therapy is effective in neuropsychiatric disorders by unknown mechanisms. Microglial toxicity plays key role in neuropsychiatric, neuroinflammatory and degenerative diseases. We examined the mechanism by which electroconvulsive seizures (ECS) regulates microglial phenotype and response to stimuli. Microglial responses were examined by morphological analysis, Iba1 and cytokine expression. ECS did not affect resting microglial phenotype or morphology but regulated their activation by Lipopolysaccharide stimulation. Microglia were isolated after ECS or sham sessions in naïve mice for transcriptome analysis. RNA sequencing identified 141 differentially expressed genes. ECS modulated multiple immune-associated gene families and attenuated neurotoxicity-associated gene expression. Blood brain barrier was examined by injecting Biocytin-TMR tracer. There was no breakdown of the BBB, nor increase in gene-signature of peripheral monocytes, suggesting that ECS effect is mainly on resident microglia. Unbiased analysis of regulatory sequences identified the induction of microglial retinoic acid receptor α (RARα) gene expression and a putative common RARα-binding motif in multiple ECS-upregulated genes. The effects of AM580, a selective RARα agonist on microglial response to LPS was examined in vitro. AM580 prevented LPS-induced cytokine expression and reactive oxygen species production. Chronic murine experimental autoimmune encephalomyelitis (EAE) was utilized to confirm the role RARα signaling as mediator of ECS-induced transcriptional pathway in regulating microglial toxicity. Continuous intracerebroventricular delivery of AM580 attenuated effectively EAE severity. In conclusion, ECS regulates CNS innate immune system responses by activating microglial retinoic acid receptor α pathway, signifying a novel therapeutic approach for chronic neuroinflammatory, neuropsychiatric and neurodegenerative diseases.
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Encefalomielite Autoimune Experimental , Microglia , Receptor alfa de Ácido Retinoico , Animais , Eletroconvulsoterapia , Lipopolissacarídeos , Camundongos , Transdução de SinaisRESUMO
We explored whether experimental autoimmune encephalomyelitis (EAE) in Biozzi mice recapitulates temporal dynamics of tissue injury, immune-pathogenesis and CNS compartmentalization occurring in progressive multiple sclerosis (MS). Chronic EAE exhibited relapsing and progressing disease, partial closure of BBB, reduced tissue inflammatory activity, and development of meningeal ectopic lymphoid tissue, directly opposing (potentially driving) spinal subpial demyelinated plaques. A T cell predominant disease during relapses transformed into a B cell predominant disease in late chronic EAE, with high serum anti-MOG reactivity. Thus, late chronic Biozzi EAE recapitulates essential features of progressive MS, and is suitable for developing disease modifying and regenerative therapies.
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Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla Crônica Progressiva/imunologia , Medula Espinal/imunologia , Animais , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Adjuvante de Freund/toxicidade , Camundongos , Camundongos Biozzi , Esclerose Múltipla Crônica Progressiva/induzido quimicamente , Esclerose Múltipla Crônica Progressiva/patologia , Medula Espinal/patologiaRESUMO
Background: Exercise training induces beneficial effects on neurodegenerative diseases, and specifically on multiple sclerosis (MS) and it's model experimental autoimmune encephalomyelitis (EAE). However, it is unclear whether exercise training exerts direct protective effects on the central nervous system (CNS), nor are the mechanisms of neuroprotection fully understood. In this study, we investigated the direct neuroprotective effects of high-intensity continuous training (HICT) against the development of autoimmune neuroinflammation and the role of resident microglia. Methods: We used the transfer EAE model to examine the direct effects of training on the CNS. Healthy mice performed HICT by treadmill running, followed by injection of encephalitogenic proteolipid (PLP)-reactive T-cells to induce EAE. EAE severity was assessed clinically and pathologically. Brain microglia from sedentary (SED) and HICT healthy mice, as well as 5-days post EAE induction (before the onset of disease), were analyzed ex vivo for reactive oxygen species (ROS) and nitric oxide (NO) formation, mRNA expression of M1/M2 markers and neurotrophic factors, and secretion of cytokines and chemokines. Results: Transfer of encephalitogenic T-cells into HICT mice resulted in milder EAE, compared to sedentary mice, as indicated by reduced clinical severity, attenuated T-cell, and neurotoxic macrophage/microglial infiltration, and reduced loss of myelin and axons. In healthy mice, HICT reduced the number of resident microglia without affecting their profile. Isolated microglia from HICT mice after transfer of encephalitogenic T-cells exhibited reduced ROS formation and released less IL-6 and monocyte chemoattractant protein (MCP) in response to PLP-stimulation. Conclusions: These findings point to the critical role of training intensity in neuroprotection. HICT protects the CNS against autoimmune neuroinflammation by reducing microglial-derived ROS formation, neurotoxicity, and pro-inflammatory responses involved in the propagation of autoimmune neuroinflammation.
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BACKGROUND: Studies have reported beneficial effects of exercise training on autoimmunity, and specifically on multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, it is unknown whether different training paradigms affect disease course via shared or separate mechanisms. OBJECTIVE: To compare the effects and mechanism of immune modulation of high intensity continuous training (HICT) versus high intensity interval training (HIIT) on systemic autoimmunity in EAE. METHODS: We used the proteolipid protein (PLP)-induced transfer EAE model to examine training effects on the systemic autoimmune response. Healthy mice performed HICT or HIIT by running on a treadmill. Lymph-node (LN)-T cells from PLP-immunized trained- versus sedentary donor mice were transferred to naïve recipients and EAE clinical and pathological severity were assessed. LN cells derived from donor trained and sedentary PLP-immunized mice were analyzed in vitro for T-cell activation and proliferation, immune cell profiling, and cytokine mRNA levels and cytokine secretion measurements. RESULTS: Both HICT and HIIT attenuated the encephalitogenicity of PLP-reactive T cells, as indicated by reduced EAE clinical severity and inflammation and tissue pathology in the central nervous system, following their transfer into recipient mice. HICT caused a marked inhibition of PLP-induced T-cell proliferation without affecting the T-cell profile. In contrast, HIIT did not alter T-cell proliferation, but rather inhibited polarization of T cells into T-helper 1 and T-helper 17 autoreactive populations. INTERPRETATION: HICT and HIIT attenuate systemic autoimmunity and T cell encephalitogenicity by distinct immunomodulatory mechanisms.
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Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/fisiologia , Animais , Feminino , Linfonodos/imunologia , Camundongos , Medula Espinal/imunologia , Medula Espinal/patologiaRESUMO
Electroconvulsive therapy is highly effective in resistant depression by unknown mechanisms. Microglial toxicity was suggested to mediate depression and plays key roles in neuroinflammatory and degenerative diseases, where there is critical shortage in therapies. We examined the effects of electroconvulsive seizures (ECS) on chronic neuroinflammation and microglial neurotoxicity. Electric brain stimulation inducing full tonic-clonic seizures during chronic relapsing-progressive experimental autoimmune encephalomyelitis (EAE) reduced spinal immune cell infiltration, reduced myelin and axonal loss, and prevented clinical deterioration. Using the transfer EAE model, we examined the effect of ECS on systemic immune response in donor mice versus ECS effect on CNS innate immune activity in recipient mice. ECS did not affect encephalitogenicity of systemic T cells, but it targeted the CNS directly to inhibit T cell-induced neuroinflammation. In vivo and ex vivo assays indicated that ECS suppressed microglial neurotoxicity by reducing inducible NOS expression, nitric oxide, and reactive oxygen species (ROS) production, and by reducing CNS oxidative stress. Microglia from ECS-treated EAE mice expressed less T cell stimulatory and chemoattractant factors. Our findings indicate that electroconvulsive therapy targets the CNS innate immune system to reduce neuroinflammation by attenuating microglial neurotoxicity. These findings signify a potentially novel therapeutic approach for chronic neuroinflammatory, neuropsychiatric, and neurodegenerative diseases.
Assuntos
Eletroconvulsoterapia/métodos , Encefalomielite Autoimune Experimental/terapia , Animais , Axônios/metabolismo , Movimento Celular , Células Cultivadas , Citocinas/metabolismo , Feminino , Camundongos , Microglia/metabolismo , Bainha de Mielina/metabolismo , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Medula Espinal/citologia , Medula Espinal/metabolismo , Linfócitos T/imunologia , Linfócitos T/fisiologiaRESUMO
OBJECTIVE: To determine the frequency and significance of concurrent glial (glial-Ab) or neuronal-surface (NS-Ab) antibodies in patients with anti-NMDA receptor (NMDAR) encephalitis. METHODS: Patients were identified during initial routine screening of a cohort (C1) of 646 patients consecutively diagnosed with anti-NMDAR encephalitis and another cohort (C2) of 200 patients systematically rescreened. Antibodies were determined with rat brain immunostaining and cell-based assays. RESULTS: Concurrent antibodies were identified in 42 patients (4% from C1 and 7.5% from C2): 30 (71%) with glial-Ab and 12 (29%) with NS-Ab. Glial-Ab included myelin oligodendrocyte glycoprotein (MOG) (57%), glial fibrillary acidic protein (GFAP) (33%), and aquaporin 4 (AQP4) (10%). NS-Ab included AMPA receptor (AMPAR) (50%), GABAa receptor (GABAaR) (42%), and GABAb receptor (8%). In 39 (95%) of 41 patients, concurrent antibodies were detected in CSF, and in 17 (41%), concurrent antibodies were undetectable in serum. On routine clinical-immunologic studies, the presence of MOG-Ab and AQP4-Ab was suggested by previous episodes of encephalitis or demyelinating disorders (8, 27%), current clinical-radiologic features (e.g., optic neuritis, white matter changes), or standard rat brain immunohistochemistry (e.g., AQP4 reactivity). GFAP-Ab did not associate with distinct clinical-radiologic features. NS-Ab were suggested by MRI findings (e.g., medial temporal lobe changes [AMPAR-Ab], or multifocal cortico-subcortical abnormalities [GABAaR-Ab]), uncommon comorbid conditions (e.g., recent herpesvirus encephalitis), atypical tumors (e.g., breast cancer, neuroblastoma), or rat brain immunostaining. Patients with NS-Ab were less likely to have substantial recovery than those with glial-Ab (5 of 10 [50%] vs 17 of 19 [89%], p = 0.03). CONCLUSIONS: Between 4% and 7.5% of patients with anti-NMDAR encephalitis have concurrent glial-Ab or NS-Ab. Some of these antibodies (MOG-Ab, AQP4-Ab, NS-Ab) confer additional clinical-radiologic features and may influence prognosis.