Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis

Abstract

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 Kv1.3 may be a therapeutic target of interest for MS and add astrocytes to the list of cells whose activation would be suppressed by inhibiting Kv1.3 in inflammatory conditions.

A common genetic variant rs2821557 in KCNA3 is linked to the severity of multiple sclerosis

“…The autoreactive T EM lymphocytes then quickly migrate to local inflammation centers due to expression of a specific repertoire of adhesion molecules and chemokine receptors, and exhibit an enhanced ability to secrete pro-inflammatory cytokines upon activation (Sallusto et al, 1999). In MS, T EM accumulate in areas of demyelination and axonal lesions, consistent with high levels of expression of Kv1.3 in these areas (Bozic et al, 2018;Rus et al, 2005). Therefore, it is likely that the higher incidence of the rapidly progressing form of MS in patients with the C allele (vs.…”

“…It is important to mention that, in addition to T EM cells, other cell types (e.g., microglia, astrocytes) contribute to immune response and neuropathogenesis in MS. Kv1.3 channels upregulation in microglia is linked to activation and conversion to M1 phenotype that is an important contributing factor to the progression of MS (Nguyen et al, 2017;Di Lucente et al, 2018). Likewise, the reactive astrocytes upregulate Kv1.3 and accumulate, along with microglia and microphages, in the areas of inflammatory lesions in EAE (Bozic et al, 2018). Although, the relationships between rs2821557 and functional properties of microglia and astrocytes were not addressed by our study, it is possible that T-to-C substitution in rs2821557 enhances immune responses by these cell types, contributing to accelerated neuropathogenesis in C allele carriers.…”

“…Multiple sclerosis (MS) is a chronic neurodegenerative disorder that is characterized by gradual myelin loss and axonal damage associated with massive infiltration of the brain with autoreactive myelin-specific CD4+ lymphocytes, as well as chronic activation of astrocytes and resident microglia (Bozic et al, 2018;Compston & Coles, 2008;Legroux & Arbour, 2015). MS instantiates in several clinical forms and typically starts as a relapsing-remitting disorder, although a rapidly progressing form without remissions (primary progressive [PP-MS]) is observed in a small percentage (10%-12%) of patients.…”

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

“…Kv1.3 blocks membrane depolarization and maintains the driving force for Ca 2+ entry by effluxing K + , which in turn participates in T cell activation, and Ca 2+ activation signaling cascade, leading to T cell proliferation and cytokine production (Wulff et al, 2009;Bozic et al, 2018). These findings suggest Kv1.3 to be a valuable therapeutic target for immunosuppression in MS and EAE (Beeton et al, 2006;Wulff and Zhorov, 2008).…”

Scorpion Toxins from Buthus martensii Karsch (BmK) as Potential Therapeutic Agents for Neurological Disorders: State of the Art and Beyond

“…In animal model of experimental autoimmune encephalitis (EAE), it has also been confirmed that the expression of Kv1.3 is significantly elevated [77]. Kv1.3 blocks membrane depolarization and maintains the driving force for Ca 2+ entry by effluxing K + , which in turn participates in T cell activation, Ca 2+ activation signaling cascade, leading to T cell proliferation and cytokine production [78,79]. These findings make Kv1.3 a valuable potential therapeutic target for immunosuppression in MS and EAE [80].…”