IL-1β disrupts blood-brain barrier development by inhibiting endothelial Wnt/β-catenin signaling.
| Title: | IL-1β disrupts blood-brain barrier development by inhibiting endothelial Wnt/β-catenin signaling. |
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| Authors: | Fetsko AR; School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA.; Sebo DJ; School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA.; Budzynski LB; School of Pharmacy, Pharmacology and Toxicology Program, University of Wisconsin-Madison, Madison, WI, USA.; Scharbarth A; School of Pharmacy, Pharmacology and Toxicology Program, University of Wisconsin-Madison, Madison, WI, USA.; Taylor MR; School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA.; School of Pharmacy, Pharmacology and Toxicology Program, University of Wisconsin-Madison, Madison, WI, USA. |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 07. Date of Electronic Publication: 2024 Feb 07. |
| Publication Type: | Preprint; Journal Article |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| Abstract: | During neuroinflammation, the proinflammatory cytokine Interleukin-1β (IL-1β) impacts blood-brain barrier (BBB) function by disrupting brain endothelial tight junctions, promoting vascular permeability, and increasing transmigration of immune cells. Here, we examined the effects of Il-1β on the in vivo development of the BBB. We generated a doxycycline-inducible transgenic zebrafish model that drives secretion of Il-1β in the CNS. To validate the utility of our model, we showed Il-1β dose-dependent mortality, recruitment of neutrophils, and expansion of microglia. Using live imaging, we discovered that Il-1β causes a significant reduction in CNS angiogenesis and barriergenesis. To demonstrate specificity, we rescued the Il-1β induced phenotypes by targeting the zebrafish il1r1 gene using CRISPR/Cas9. Mechanistically, we determined that Il-1β disrupts BBB development by decreasing Wnt/β-catenin transcriptional activation in brain endothelial cells. Given that several neurodevelopmental disorders are associated with inflammation, our findings support further investigation into the connections between proinflammatory cytokines, neuroinflammation, and neurovascular development. |
| Competing Interests: | Declaration of Interests The authors declare no competing interests. |
| Comments: | Update in: iScience. 2024 Mar 30;27(5):109651. doi: 10.1016/j.isci.2024.109651.. (PMID: 38638574) |
| Grant Information: | R01 NS116043 United States NS NINDS NIH HHS; T32 GM008349 United States GM NIGMS NIH HHS; T32 GM135066 United States GM NIGMS NIH HHS |
| Entry Date(s): | Date Created: 20231218 Latest Revision: 20240506 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10723338 |
| DOI: | 10.1101/2023.12.04.569943 |
| PMID: | 38106202 |
| Database: | MEDLINE |
Preprint; Journal Article