Rebecca A. Russell6, Jakub Chojnacki6, Daniel M. Jones6, Errin Johnson, Thao Do, Christian Eggeling, Sergi Padilla-Parra, Quentin J. Sattentau7,'Correspondence information about the author Quentin J. SattentauEmail the author Quentin J. Sattentau 6Co-first author 7Lead Contact Open Access DOI: http://dx.doi.org/10.1016/j.celrep.2017.01.027 | Open access funded by Wellcome Trust
Highlights •Astrocytes may endocytose virions from cell-free or cell-cell sources •HIV-1 virions do not fuse with astrocytes and astrocytes are not infected •Astrocytes cluster with HIV-1-infected macrophages •Astrocytes engulf macrophage material, including HIV-1-infected debris
Dennis W. Simon, Mandy J. McGeachy, Hülya Bayır, Robert S. B. Clark, David J. Loane & Patrick M. Kochanek AffiliationsContributionsCorresponding author Nature Reviews Neurology (2017) doi:10.1038/nrneurol.2017.13 Published online 10 February 2017
The 'silent epidemic' of traumatic brain injury (TBI) has been placed in the spotlight as a result of clinical investigations and popular press coverage of athletes and veterans with single or repetitive head injuries. Neuroinflammation can cause acute secondary injury after TBI, and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials. In this Review, we therefore propose a new framework of targeted immunomodulation after TBI for future exploration. Our framework incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structuring our discussion around the dynamics of the immune response to TBI — from initial triggers to chronic neuroinflammation — we consider the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration. We summarize both animal model and human studies, with clinical data explicitly defined throughout this Review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including concepts of inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. Moreover, we highlight findings that could offer novel therapeutic targets for translational and clinical research, assimilate evidence from other brain injury models, and identify outstanding questions in the field.
Highlights • Central nervous and immune systems interact constantly through multiple pathways. • Peripheral immunosenescence and “inflammaging” may contribute to neuroinflammation. • Increase in glial activation has detrimental effects on neuroprotective function. • Neuroinflammation leads to deficiency in neurotrophins, diminishing neuroplasticity. • Behavioral interventions mitigate neuroinflammation and maintain neuroplasticity.
Limbic encephalitis (LE) is an inflammatory brain disorder that predominantly involves the gray matter of the medial temporal lobes, resulting in mood and behavioral changes, seizures, and difficulty in forming new memories, often with retrograde memory loss.1 In most patients, the presence of an inflammatory process in the medial temporal lobes and hippocampi is visible on MRI fluid-attenuated inversion recovery (FLAIR) sequences and supported by demonstration of pleocytosis in the CSF.2–4 Nevertheless, several infections, systemic inflammatory diseases, and autoimmune mechanisms may lead to this syndrome (table). The recent descriptions of neuronal autoantibodies associated with LE have led to a dependency on antibody testing. However, many patients with autoimmune LE can be diagnosed on clinical grounds.1 This includes careful assessment of the syndrome and ancillary tests that are available in most institutions, such as routine CSF analysis with viral studies, brain MRI, and EEG, which usually shows unilateral or bilateral temporal lobe epileptic discharges or slow activity (for a review on the clinical diagnosis of LE, see reference 1). There are few infectious agents that predominantly affect the medial temporal lobes, and most of the other potential causes of LE shown in the table can be excluded after a thorough clinical history and examination. Some symptoms may even suggest the immunologic subtype of LE (e.g., faciobrachial dystonic seizures and leucine-rich glioma-inactivated 1 [LGI1] antibodies).5
A shock-and-kill approach involving the simultaneous treatment of HIV-1–infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1–infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3. Results show that prostratin and bryostatin-1 can significantly damage the integrity of an endothelial monolayer. Moreover, prostratin and bryostatin-1 induce secretion of some proinflammatory cytokines and an increase of ICAM-1 expression. Additional studies demonstrated that prostratin and bryostatin-1 also affect adhesion and transmigration of CD4+ and CD8+ T cells as well as monocytes in an in vitro human blood–brain barrier (BBB) model. Prostratin and bryostatin-1 could thus be considered as potent regulators of BBB permeability and inflammation that influence leukocyte transport across the BBB. Altogether, these findings contribute to a better understanding of the potential risks and benefits of using a shock-and-kill approach with LRAs on the normal physiological functions of the BBB.
Abstract While a number of endogenous risk factors including age and genetics are established for Alzheimer’s disease (AD), identification of acquired, potentially preventable or treatable causes, remains limited. In this paper, we review three epidemiologic case studies and present extensive biologic, immunologic and anatomic evidence to support a novel hypothesis that Bordetella pertussis (BP), the bacterium better known to cause whooping cough, is an important potential cause of AD. Cross-cultural documentation of nasopharyngeal subclinical BP colonization reflecting BP-specific mucosal immunodeficiency, proximate anatomy of intranasal mucosal surfaces to central nervous system (CNS) olfactory pathways, and mechanisms by which BP and BP toxin account for all hallmark pathology of AD are reviewed, substantiating biologic plausibility. Notably, respiratory BP infection and BP toxin secreted from subclinical BP colonization can account for the initiation and accumulation of amyloid β plaques and tau tangles. Additional mechanisms consistent with the immunobiologic effects of subclinical BP colonization include microglial activation and inflammation, atrophy and neurodegeneration, excitotoxicity, distinctive anatomic distribution and sequential spread of disease, impaired glucose utilization, and other characteristic CNS pathology of AD. We conclude by assessing the evidence for causation against the Bradford Hill criteria, and advocate for further investigation into the potential role of BP in the etiology of AD.
This postmortem study evaluates whether alterations in aquaporin-4 expression or loss of perivascular aquaporin-4 localization are associated with cognition and
Publication date: November 2016 Source:Pharmacological Research, Volume 113, Part B Author(s): Akvilė Jarmalavičiūtė, Augustas Pivoriūnas Exosomes are extracellular vesicles that can transfer biological information over long distances affecting normal and pathological processes throughout organism. It is known that very often composition and therapeutic properties of exosomes depends on cell type and its physiological state. Thus, depending on tissue of origin and physiological context exosomes may act as promoters, or suppressors of pathological processes in CNS. From the therapeutic perspective, the most promising cellular sources of exosomes are mesenchymal stem cells, dendritic cells and inducible pluripotent stem cells. In this review, we will summarize the current state of knowledge on the molecular mechanisms underlying neuroprotective actions of exosomes derived from these cells. New therapies for the neurodegenerative disorders are often halted by the inability of drugs to cross blood–brain barrier. In this respect exosomes have a critical advantage, because they can cross blood–brain barrier. Despite the great importance, surprisingly little is known about mechanistic details of this process. Therefore we will discuss some recent findings that may explain mechanisms of exosomal entry into the brain. Graphical abstract
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Late-onset AD (LOAD), is the most common form of Alzheimer's disease, representing about >95..
Publication date: 6 March 2017 Source:Neuroscience, Volume 344 Author(s): Muhammad Saad Yousuf, Kasia Zubkow, Gustavo Tenorio, Bradley Kerr Patients with multiple sclerosis (MS) often complain of neuropathic pain. According to the Gate Control Theory of Pain, spinal networks of GABAergic inhibitory interneurons are important in modulating nociceptive inputs from the periphery. Na+–K+–2Cl− co-transporter 1 (NKCC1) and K+–Cl− co-transporter 2 (KCC2) generally dictate the tone of GABA/glycine inhibition by regulating intracellular chloride concentrations. In this study, we investigated the role of NKCC1 and KCC2 in neuropathic pain observed in the animal model, experimental autoimmune encephalomyelitis (EAE), a commonly used model to study the pathophysiology of MS. Quantitative real-time polymerase chain reactions (qRT-PCR) analysis revealed no change in NKCC1 mRNA transcripts in dorsal root ganglia throughout EAE disease course. However, NKCC1 and KCC2 mRNA levels in the dorsal spinal cord were significantly reduced at disease onset and peak only to recover by the chronic time point. Similarly, Western blot data revealed a significant downregulation of NKCC1 and KCC2 in the dorsal spinal cord at disease onset but an upregulation of NKCC1 protein in the dorsal root ganglia at this time point. Treatment with bumetanide, an NKCC inhibitor, had no effect on mechanical hypersensitivity seen in mice with EAE even though it reversed the changes in the levels of NKCC1 and KCC2. We noted that bumetanide treatment, while effective at reversing the changes in monomeric KCC2 levels was ineffective at reversing the changes in oligomeric KCC2 which remained repressed. These results indicate that mechanical hypersensitivity in EAE is not mediated by altered levels of NKCC1.
Publication date: 27 March 2017 Source:Neuroscience, Volume 346 Author(s): Aparna Patra, Xiaodi Chen, Grazyna B. Sadowska, Jiyong Zhang, Yow-Pin Lim, James F. Padbury, William A. Banks, Barbara S. Stonestreet Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1β (IL-1β) is a key mediator of inflammatory responses and elevated IL-1β levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood–brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia–reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1β monoclonal antibody (mAb) reduce IL-1β transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1β mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1β protein expressed from IL-1β pGEX-2T vectors in Escherichia coli (E. coli) BL-21 cells was produced, purified, and radiolabeled with 125I. BBB permeability was quantified using the blood-to-brain transfer constant (Ki ) with 125I-radiolabeled-IL-1β. Increases in anti-IL-1β mAb were observed in the brain of the mAb-treated group (P <0.001). Blood-to-brain transport of 125I-IL-1β was lower (P <0.04) across brain regions in the anti-IL-1β mAb-treated than placebo-treated ischemic fetuses. Plasma 125I-IL-1β counts were higher (P <0.001) in the anti-IL-1β mAb- than placebo-treated ischemic fetuses. Systemic infusions of anti-IL-1β mAb reduce IL-1β transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic pro-inflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy. Graphical abstract
Advances in translational neuroimmunology over the last two decades have revolutionized the treatment of relapsing forms of multiple sclerosis. A pathological hallmark of multiple sclerosis is the presence of leukocytes in the areas of disease activity in the CNS. Natalizumab inhibits the trafficking of lymphocytes from the blood into the brain and spinal cord by blocking the adhesion molecule α4-integrin. Representing the enormous success of a molecular targeted approach, natalizumab was the first mAb approved for the treatment of relapsing–remitting multiple sclerosis. However, only a few months after its approval, natalizumab was withdrawn from the market because of an unanticipated life threatening adverse effect: progressive multifocal leukoencephalopathy. Natalizumab was later reintroduced with required adherence to a strict monitoring program. In this article, we review the bench-to-bedside journey of natalizumab, along with the lessons learned from postmarketing studies.
Objective: To report 10 patients with limbic encephalitis (LE) and adenylate kinase 5 autoantibodies (AK5-Abs). Methods: We conducted a retrospective study in a cohort of 50 patients with LE with uncharacterized autoantibodies and identified a specific target using immunohistochemistry, Western blotting, immunoprecipitation, mass spectrometry, and cell-based assay. Results: AK5 (a known autoantigen of LE) was identified as the target of antibodies in the CSFs and sera of 10 patients with LE (median age 64 years; range 57–80), which was characterized by subacute anterograde amnesia without seizure and sometimes preceded by a prodromal phase of asthenia or mood disturbances. Anterograde amnesia can be isolated, but some patients also complained of prosopagnosia, paroxysmal anxiety, or abnormal behavior. No associated cancer was observed. All 10 patients had bilateral hippocampal hypersignal on a brain MRI. CSF analysis generally showed a mild pleiocytosis with elevated immunoglobulin G index and oligoclonal bands, as well as high levels of tau protein with normal concentration of Aβ42 and phospho-tau, suggesting a process of neuronal death. Except for one patient, clinical response to immunotherapy was unfavorable, with persistence of severe anterograde amnesia. Two patients evolved to severe cognitive decline. Hippocampal atrophy was observed on control brain MRI. Using in vitro tests on hippocampal neurons, we did not identify clues suggesting a direct pathogenic role of AK5-Abs. Conclusions: AK5-Abs should be systematically considered in aged patients with subacute anterograde amnesia. Recognition of this disorder is important to develop new treatment strategies to prevent irreversible limbic damage.
The Multiple Sclerosis Association of America (MSAA) is a leading resource for the entire MS community, improving lives today through vital services and support.
What Einstein did for physics, a Spaniard named Santiago Ramón y Cajal did for neuroscience more than a century ago. Back in the 1890s, Cajal produced a
The therapeutic mode of action of dimethyl fumarate (DMF), approved for treating patients with relapsing-remitting multiple sclerosis, is not fully understood. Recently, we and others demonstrated that Ab-independent functions of distinct B cell subsets are important in mediating multiple sclerosis (MS) relapsing disease activity. Our objective was to test whether and how DMF influences both the phenotype and functional responses of disease-implicated B cell subsets in patients with MS. High-quality PBMC were obtained from relapsing-remitting MS patients prior to and serially after initiation of DMF treatment. Multiparametric flow cytometry was used to monitor the phenotype and functional response-profiles of distinct B cell subsets. Total B cell counts decreased following DMF treatment, largely reflecting losses of circulating mature/differentiated (but not of immature transitional) B cells. Within the mature B cell pool, DMF had a greater impact on memory than naive B cells. In keeping with these in vivo effects, DMF treatment in vitro remarkably diminished mature (but not transitional B cell) survival, mediated by inducing apoptotic cell death. Although DMF treatment (both in vivo and in vitro) minimally impacted B cell IL-10 expression, it strongly reduced B cell expression of GM-CSF, IL-6, and TNF-α, resulting in a significant anti-inflammatory shift of B cell response profiles. The DMF-mediated decrease in B cell proinflammatory cytokine responses was further associated with reduced phosphorylation of STAT5/6 and NF-κB in surviving B cells. Together, these data implicate novel mechanisms by which DMF may modulate MS disease activity through shifting the balance between pro- and anti-inflammatory B cell responses.
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