Mice Heterozygous for the Sodium Channel Scn8a (Nav1.6) Have Reduced Inflammatory Responses During EAE and Following LPS Challenge.

Barakat Alrashdi,Bassel Dawod,Jean S Marshall,Stefanie Kuerten,Sabine Tacke,Patrice D Côté

doi:10.3389/fimmu.2021.533423

Abstract

Voltage gated sodium (Nav) channels contribute to axonal damage following demyelination in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). The Nav1.6 isoform has been implicated as a primary contributor in this process. However, the role of Nav1.6 in immune processes, critical to the pathology of both MS and EAE, has not been extensively studied. EAE was induced with myelin oligodendrocyte (MOG35-55) peptide in Scn8admu/+ mice, which have reduced Nav1.6 levels. Scn8admu/+ mice demonstrated improved motor capacity during the recovery and early chronic phases of EAE relative to wild-type animals. In the optic nerve, myeloid cell infiltration and the effects of EAE on the axonal ultrastructure were also significantly reduced in Scn8admu/+ mice. Analysis of innate immune parameters revealed reduced plasma IL-6 levels and decreased percentages of Gr-1high/CD11b+ and Gr-1int/CD11b+ myeloid cells in the blood during the chronic phase of EAE in Scn8admu/+ mice. Elevated levels of the anti-inflammatory cytokines IL-10, IL-13, and TGF-β1 were also observed in the brains of untreated Scn8admu/+ mice. A lipopolysaccharide (LPS) model was used to further evaluate inflammatory responses. Scn8admu/+ mice displayed reduced inflammation in response to LPS challenge. To further evaluate if this was an immune cell-intrinsic difference or the result of changes in the immune or hormonal environment, mast cells were derived from the bone marrow of Scn8admu/+ mice. These mast cells also produced lower levels of IL-6, in response to LPS, compared with those from wild type mice. Our results demonstrate that in addition to its recognized impact on axonal damage, Nav1.6 impacts multiple aspects of the innate inflammatory response.

Highlights

Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects the central nervous system (CNS) [1] where it causes myelin loss that eventually leads to permanent disability in the majority of patients
Our results demonstrate that a reduction in Nav1.6/Scn8a expression has a significant inhibitory effect on the inflammatory response through a mechanism associated with dysregulated inflammatory cytokine responses
To evaluate the impact of reduced expression of Scn8a, the gene that encodes the alpha subunit of the Nav1.6 channel, on inflammation in the EAE model, we used Scn8admu/+ heterozygous mice and wild type Scn8a+/+ littermates housed in the same cage environment

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects the central nervous system (CNS) [1] where it causes myelin loss that eventually leads to permanent disability in the majority of patients. T and B cell function, as well as innate immune responses, are believed to play an important role in neuronal damage and loss of the myelin in the CNS [4]. The innate immune and inflammatory processes required to initiate and sustain disease are driven by a variety of cytokines and chemokines that include a pro-inflammatory cytokine cascade involving TNF and IL-6 [10]. These cytokines activate immune effector cells and promote their migration partly through the enhanced expression of adhesion molecules on vascular endothelium [10, 11]. A number of regulatory cytokines, such as IL-10 help modulate the inflammatory process [12, 13]

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