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Multiple Sclerosis (MS) is an immune-mediated disease that results in major locomotor deficits. However, recent studies have revealed that fatigue, slow processing speed, and memory impairment are the top variables impacting employment status for MS patients. These suggest that cognitive effects may have a greater impact on productivity, lifestyle, and quality of life than do disease-related motor deficits. However, these debilitating non-locomotive effects have been largely overlooked in rodent models of the disease, such as experimental autoimmune encephalomyelitis (EAE). We hypothesized that murine EAE can also be used to assess non-locomotive dysfunctions (mood, sociability, muscle strength, and balance), as well as potential biases in these dysfunctions due to sex and/or strain. We actively immunized male and female C57BL/6 (B6) and SJL mice for EAE and evaluated their performance on the Deacon's weight grip test, Kondziela's inverted screen test, Hall's rope grip test, manual von Frey test for somatic nociception, and a three-chamber social preference paradigm. We hypothesized that EAE progression is associated with changes in muscle strength, balance, pain, and sociability and that these variations are linked to sex and/or strain. Our results indicate that strain but not sex influenced differences in muscle strength and balance during EAE, and both sex and strain have an impact on mechanical nociception, regardless of EAE disease status. Furthermore, both sex and strain had complex effects on differences in sociability. In conclusion, testing these additional modalities during EAE helps to unveil other signs and symptoms that could be used to determine the efficacy of a drug or treatment in the modulation of a MS-like behavior.

Considerable clinical evidence supports that increased blood–brain barrier (BBB) permeability is linked to immune extravasation of CNS parenchyma during neuroinflammation. Although BBB permeability and immune extravasation are known to be provoked by vascular endothelial growth factor-A (i.e., VEGF-A) and C-X-C motif chemokine ligand 12 (CXCL12), respectively, the mechanisms that link both processes are still elusive. The interleukin-20 (i.e., IL-20) cytokine signaling pathway was previously implicated in VEGF-mediated angiogenesis and is known to induce cellular response by way of signaling through IL-20 receptor subunit β (i.e., IL-20RB). Dysregulated IL-20 signaling is implicated in many inflammatory pathologies, but it’s contribution to neuroinflammation has yet to be reported. We hypothesize that the IL-20 cytokine, and the IL cytokine subfamily more broadly, play a key role in CNS neuroinflammation by signaling through IL-20RB, induce VEGF activity, and enhance both BBB-permeability and CXCL12-mediated immune extravasation. To address this hypothesis, we actively immunized IL-20RB–/– mice and wild-type mice to induce experimental autoimmune encephalomyelitis (EAE) and found that IL-20RB–/– mice showed amelioration of disease progression compared to wild-type mice. Similarly, we passively immunized IL-20RB–/– mice and wild-type mice with myelin-reactive Th1 cells from either IL-20RB–/– and wild-type genotype. Host IL-20RB–/– mice showed lesser disease progression than wild-type mice, regardless of the myelin-reactive Th1 cells genotype. Using multianalyte bead-based immunoassay and ELISA, we found distinctive changes in levels of pro-inflammatory cytokines between IL-20RB–/– mice and wild-type mice at peak of EAE. We also found detectable levels of all cytokines of the IL-20 subfamily within CNS tissues and specific alteration to IL-20 subfamily cytokines IL-19, IL-20, and IL-24, expression levels. Immunolabeling of CNS region-specific microvessels confirmed IL-20RB protein at the spinal cord microvasculature and upregulation during EAE. Microvessels isolated from macaques CNS tissues also expressed IL-20RB. Moreover, we identified the expression of all IL-20 receptor subunits: IL-22 receptor subunit α-1 (IL-22RA1), IL-20RB, and IL-20 receptor subunit α (IL-20RA) in human CNS microvessels. Notably, human cerebral microvasculature endothelial cells (HCMEC/D3) treated with IL-1β showed augmented expression of the IL-20 receptor. Lastly, IL-20-treated HCMEC/D3 showed alterations on CXCL12 apicobasal polarity consistent with a neuroinflammatory status. This evidence suggests that IL-20 subfamily cytokines may signal at the BBB via IL-20RB, triggering neuroinflammation.

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