| First Author | Dayton JR | Year | 2021 |
| Journal | Front Cell Neurosci | Volume | 15 |
| Pages | 683687 | PubMed ID | 34557075 |
| Mgi Jnum | J:311194 | Mgi Id | MGI:6765671 |
| Doi | 10.3389/fncel.2021.683687 | Citation | Dayton JR, et al. (2021) Expression of IL-20 Receptor Subunit beta Is Linked to EAE Neuropathology and CNS Neuroinflammation. Front Cell Neurosci 15:683687 |
| abstractText | 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 beta (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 alpha-1 (IL-22RA1), IL-20RB, and IL-20 receptor subunit alpha (IL-20RA) in human CNS microvessels. Notably, human cerebral microvasculature endothelial cells (HCMEC/D3) treated with IL-1beta 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. |
