Mediation of Protection and Recovery From Experimental Autoimmune Encephalomyelitis by Macrophages Expressing the Human Voltage-Gated Sodium Channel NaV1.5

Abstract

Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic disability in young adults. Despite treatment, progressive tissue injury leads to accumulation of disability in many patients. Here, our goal was to develop an immune-mediated strategy to promote tissue repair and clinical recovery in an MS animal model. We previously demonstrated that a variant of the voltage-gated sodium channel NaV1.5 is expressed intracellularly in human macrophages, and that it regulates cellular signaling. This channel is not expressed in mouse macrophages, which has limited the study of its functions. To overcome this obstacle, we developed a novel transgenic mouse model (C57BL6), in which the human macrophage NaV1.5 splice variant is expressed in vivo in mouse macrophages. These mice were protected from experimental autoimmune encephalomyelitis, the mouse model of MS. During active inflammatory disease, NaV1.5-positive macrophages were found in spinal cord lesions where they formed phagocytic cell clusters; they expressed markers of alternative activation during recovery. NaV1.5-positive macrophages that were adoptively transferred into wild-type recipients with established experimental autoimmune encephalomyelitis homed to lesions and promoted recovery. These results suggest that NaV1.5-positive macrophages enhance recovery from CNS inflammatory disease and could potentially be developed as a cell-based therapy for the treatment of MS.

Pharmacological and nutritional targeting of voltage-gated sodium channels in the treatment of cancers

“…The intracellular Na V 1.5 channel was shown to enhance endosomal acidification and phagocytosis (Carrithers et al, 2007), Ca 2+ signaling, and phenotypic differentiation in human macrophages (Carrithers et al, 2011). The same group later demonstrated that SCN5A was expressed as a new splice variant lacking exon 25, resulting in a deletion of 18 amino acids in domain III (Rahgozar et al, 2013), generating non-selective outward currents and small inward currents in a heterologous expression system (Jones et al, 2014).…”

Human Macrophage SCN5A Activates an Innate Immune Signaling Pathway for Antiviral Host Defense

“…Because of an exon deletion in the extracellular selectivity filter, channel activation does not elicit typical action potentials as in excitable tissues but does mediate ionic flux in response to pharmacological stimulation. Because this channel is not expressed in murine macrophages, in vivo characterization has been performed in a knock-in transgenic model (7).…”

In silico drug repurposing in COVID-19: A network-based analysis

“…In this context, SCN5A inhibitors may contribute to controlling both systemic inflammation and viral infection. Other studies reported that macrophages present an anti-inflammatory phenotype in mice expressing human SCN5A [70] .…”