Kir 4.1 inward rectifier potassium channel is upregulated in astrocytes in a murine multiple sclerosis model (original) (raw)
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Neurochemical research, 2018
Kv1.3 is a voltage gated potassium channel that has been implicated in pathophysiology of multiple sclerosis (MS). In the present study we investigated temporal and cellular expression pattern of this channel in the lumbar part of spinal cords of animals with experimental autoimmune encephalomyelitis (EAE), animal model of MS. EAE was actively induced in female Dark Agouti rats. Expression of Kv1.3 was analyzed at different time points of disease progression, at the onset, peak and end of EAE. We here show that Kv1.3 increased by several folds at the peak of EAE at both gene and protein level. Double immunofluorescence analyses demonstrated localization of Kv1.3 on activated microglia, macrophages, and reactive astrocytes around inflammatory lesions. In vitro experiments showed that pharmacological block of Kv1.3 in activated astrocytes suppresses the expression of proinflammatory mediators, suggesting a role of this channel in inflammation. Our results support the hypothesis that K...
The Potassium Channel Kv1.5 Expression Alters During Experimental Autoimmune Encephalomyelitis
Neurochemical Research, 2019
Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease with an autoimmune component. It was suggested that potassium channels, which are involved in crucial biological functions may have a role in different diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE). It was shown that voltage-gated potassium channels Kv1.5 are responsible for fine-tuning in the immune physiology and influence proliferation and differentiation in microglia and astrocytes. Here, we explored the cellular distribution of the Kv1.5 channel, together with its transcript and protein expression in the male rat spinal cord during different stages of EAE. Our results reveal a decrease of Kv1.5 transcript and protein level at the peak of disease, where massive infiltration of myeloid cells occurs, together with reactive astrogliosis and demyelination. Also, we revealed that the presence of this channel is not found in infiltrating macrophages/microglia during EAE. It is interesting to note that Kv1.5 channel is expressed only in resting microglia in the naïve animals. Predominant expression of Kv1.5 channel was found in the astrocytes in all experimental groups, while some vimentin + cells, resembling macrophages, are devoid of Kv1.5 expression. Our results point to the possible link between Kv1.5 channel and the pathophysiological processes in EAE.
The Journal of Rehabilitation Research and Development, 2006
Inflammatory tissue damage and the presence of reactive immunocompetent T lymphocytes, macrophages, microglia, and dendritic cells (DCs) are characteristic features in the human chronic inflammatory demyelinating disease, multiple sclerosis (MS). Together, these cells orchestrate the inflammation and immunopathogenesis underlying the MS autoimmune disease processes and all up-regulate the same voltage-gated potassium (K v ) channel, K v 1.3, when fully activated. Only microglia, which mediate central nervous system (CNS) inflammatory processes (possibly playing a dual role of CNS protection and mediation of neuroinflammation/ neurodegeneration), and DC, which are pivotal to the induction of T cell responses, express the distinct K v 1.5 prior to K v 1.3 upregulation. Although the precise functional roles of first K v 1.5 and then K v 1.3 channels are unclear, their differential expression is likely a common mechanism used by both microglia and DC, revealing K v 1.5 (in addition to K v 1.3) as a potentially important target for the development of new immunomodulatory therapies in MS.
K+ channel alterations in the progression of experimental autoimmune encephalomyelitis
Neurobiology of Disease, 2012
Voltage-gated K + (Kv) channels play critical roles not only in regulating synaptic transmission and intrinsic excitability of neurons, but also in controlling the function and proliferation of other cells in the central nervous system (CNS). The non-specific Kv channel blocker, 4-AminoPyridine (4-AP) (Dalfampridine, Ampyra®), is currently used to treat multiple sclerosis (MS), an inflammatory demyelinating disease. However, little is known how various types of Kv channels are altered in any inflammatory demyelinating diseases. By using established animal models for MS, experimental autoimmune encephalomyelitis (EAE), we report that expression and distribution patterns of Kv channels are altered in the CNS correlating with EAE severity. The juxtaparanodal (JXP) targeting of Kv1.2/Kvβ2 along myelinated axons is disrupted within demyelinated lesions in the white matter of spinal cord in EAE. Moreover, somatodendritic Kv2.1 channels in the motor neurons of lower spinal cord significantly decrease correlating with EAE severity. Interestingly, Kv1.4 expression surrounding lesions is markedly up-regulated in the initial acute phase of both EAE models. Its expression in glial fibrillary acidic protein (GFAP)-positive astrocytes further increases in the remitting phase of remitting-relapsing EAE (rrEAE), but decreases in late chronic EAE (chEAE) and the relapse of rrEAE, suggesting that Kv1.4-positive astrocytes may be neuroprotective. Taken together, our studies reveal myelin-dependent and -independent alterations of Kv channels in the progression of EAE and lay a solid foundation for future study in search of a better treatment for MS.
Proceedings of the National Academy of Sciences, 2005
postmortem MS brain inflammatory infiltrates. The expression pattern revealed not only Kv1.3 ؉ T cells in the perivenular infiltrate but also high expression in the parenchyma of demyelinated MS lesions and both normal appearing gray and white matter. These cells were uniformly chemokine receptor 7 negative (CCR7 ؊ ), consistent with an effector memory phenotype. Using doublelabeling immunohistochemistry and confocal microscopy, we demonstrated colocalization of Kv1.3 with CD3, CD4, CD8, and some CD68 cells. The expression patterns mirrored in vitro experiments showing polarization of Kv1.3 to the immunological synapse. Kv1.3 was expressed in low to moderate levels on CCR7 ؉ central memory T cells from cerebrospinal fluid, but, when these cells were stimulated in vitro, they rapidly became Kv1.3 high ͞CCR7 ؊ TEM, suggesting that a subset of cerebrospinal fluid cells existed in a primed state ready to become T EM. These studies provide further rationale for the use of specific Kv1.3 antagonists in MS. lymphocytes ͉ macrophages ͉ cerebrospinal fluid ͉ effector memory
Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis
New England Journal of Medicine, 2012
Background Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known. Methods We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo. Results Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum. Conclusions KIR4.1 is a target of the autoantibody response in a subgroup of persons with multiple sclerosis. (Funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft.
The Lancet Neurology, 2014
Background-Antibody-dependent pathogenicity is suggested in multiple sclerosis (MS) by intrathecal immunoglobulin production, IgG and complement deposition in the most common immunopathological lesion subtype (pattern II), and by a recent report that 47% of MS patients' sera contain a glial potassium-channel-specific-IgG(inwardly-rectifying, Kir4.1). Our study's aims were to determine, in MS serum and CSF, the frequency and specificity of Kir4.1-binding-IgG and, in demyelinating MS lesions, whether Kir4.1-immunoreactivity is retained or lost. Methods-We tested by ELISA(Kir4.1-peptide 83-120) sera from 286 clinically and geographically diverse MS patients (229 population-based and 57 clinic-based),99 healthy controls and 109 disease controls, and cerebrospinal fluid [CSF] from 25 MS and 22 controls. CSFs and clinic-based MS-subset serum (50)were tested on functional Kir4.1-expressing cells, using methodologies validated for detecting clinically-pertinent neural plasma membrane-reactive autoantibodies: immunofluorescence and immunoprecipitation (solubilized recombinant human Kir4.1). We evaluated Kir4.1-immunoreactivity in brain from 15 archival histopathologically
Brain Communications
Multiple sclerosis is an autoimmune disease of the central nervous system (CNS). Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium (Kir) channel 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sclerosis. Kir4.1 is expressed in the CNS but also in peripheral tissues, raising concerns about the CNS-specificity of such autoreactivity. Immunization of C57Bl6/J female mice with the e1 peptide (amino-acids 83-120 of Kir4.1) induced anti-e1 immunoglobulin G (IgG) and T cell responses, and promoted demyelinating encephalomyelitis with B cell CNS enrichment in leptomeninges and T cells/macrophages in CNS parenchyma from forebrain to spinal cord, mostly in the white matter. Within our cohort of multiple sclerosis patients (n = 252), six percent exhibited high anti-e1 IgG levels in serum as compared to 0.7% in the control cohort (n = 127; P = 0.015). Immunolabeling of Kir4.1-exp...
Journal of Neurochemistry, 2006
Transgenic mice expressing the superoxide dismutase G93A mutation (SOD1(G93A)) were used to investigate the role of glial inwardly rectifying K(+) (Kir)4.1 channels, which buffer extracellular K(+) increases in response to neuronal excitation. A progressive decrease in Kir4.1 immunoreactivity was observed predominantly in the ventral horn of SOD1(G93A) mutants. Immunoblotting of spinal cord extracts mirrored these changes by showing a loss of Kir4.1 channels from presymptomatic stages onwards. Kir4.1 channels were found to be expressed in the spinal cord grey matter, targetting astrocytes and clustering around capillaries, supporting their role in clearance of extracellular K(+). To understand the functional implications of extracellular K(+) increases, we challenged the NSC34 motor neurone cell line with increasing extracellular K(+) concentrations. Exposure to high extracellular K(+) induced progressive motor neurone cell death. We suggest that loss of Kir4.1 impairs perineural K(+) homeostasis and may contribute to motor neurone degeneration in SOD1(G93A) mutants by K(+) excitotoxic mechanisms.
Pharmacology & Therapeutics, 2006
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination, with a relative sparing of axons. In MS patients, many neurologic signs and symptoms have been attributed to the underlying conduction deficits. The idea that neurologic function might be improved if conduction could be restored in CNS demyelinated axons led to the testing of potassium (K + ) channel blockers as a symptomatic treatment. To date, only 2 broad-spectrum K + channel blockers, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP), have been tested in MS patients. Although both 4-AP and 3,4-DAP produce clear neurologic benefits, their use has been limited by toxicity.