PMID- 34557075 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220812 IS - 1662-5102 (Print) IS - 1662-5102 (Electronic) IS - 1662-5102 (Linking) VI - 15 DP - 2021 TI - Expression of IL-20 Receptor Subunit beta Is Linked to EAE Neuropathology and CNS Neuroinflammation. PG - 683687 LID - 10.3389/fncel.2021.683687 [doi] LID - 683687 AB - 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. CI - Copyright (c) 2021 Dayton, Yuan, Pacumio, Dorflinger, Yoo, Olson, Hernandez-Suarez, McMahon and Cruz-Orengo. FAU - Dayton, Jacquelyn R AU - Dayton JR AD - Department of Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA, United States. FAU - Yuan, Yinyu AU - Yuan Y AD - Department of Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA, United States. FAU - Pacumio, Lisa P AU - Pacumio LP AD - Department of Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA, United States. FAU - Dorflinger, Bryce G AU - Dorflinger BG AD - Department of Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA, United States. FAU - Yoo, Samantha C AU - Yoo SC AD - Department of Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA, United States. FAU - Olson, Mariah J AU - Olson MJ AD - Department of Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA, United States. FAU - Hernandez-Suarez, Sara I AU - Hernandez-Suarez SI AD - Department of Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA, United States. AD - Bayer School of Natural and Environmental Sciences, Duquesne University of the Holy Spirit, Pittsburgh, PA, United States. FAU - McMahon, Moira M AU - McMahon MM AD - Department of Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA, United States. AD - Department of Molecular and Cell Biology, College of Letters and Science, University of California, Berkeley, Berkeley, CA, United States. FAU - Cruz-Orengo, Lillian AU - Cruz-Orengo L AD - Department of Anatomy, Physiology and Cell Biology, University of California, Davis, Davis, CA, United States. LA - eng GR - P30 ES023513/ES/NIEHS NIH HHS/United States GR - R21 NS111431/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20210907 PL - Switzerland TA - Front Cell Neurosci JT - Frontiers in cellular neuroscience JID - 101477935 PMC - PMC8452993 OTO - NOTNLM OT - HCMEC/D3 cells OT - IL-20 subfamily OT - MOG-Th1 cells OT - experimental autoimmune encephalomyelitis OT - microvessel COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/09/25 06:00 MHDA- 2021/09/25 06:01 PMCR- 2021/01/01 CRDT- 2021/09/24 07:05 PHST- 2021/03/21 00:00 [received] PHST- 2021/08/13 00:00 [accepted] PHST- 2021/09/24 07:05 [entrez] PHST- 2021/09/25 06:00 [pubmed] PHST- 2021/09/25 06:01 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fncel.2021.683687 [doi] PST - epublish SO - Front Cell Neurosci. 2021 Sep 7;15:683687. doi: 10.3389/fncel.2021.683687. eCollection 2021.