Other
24 Authors
- Lu S,
- Guo L,
- Rich BE,
- Fang D,
- Fujinami RS,
- Zhang B,
- Lane TE,
- Thomas KR,
- Zhu W,
- Odelberg SJ,
- Davis CT,
- Pryor RJ,
- Lei K,
- Sorensen LK,
- Winter JM,
- Mueller AL,
- Shi DS,
- Tong Z,
- Doty DJ,
- Zhao H,
- Grossmann AH,
- Zhu N,
- Sun Z,
- Dickey LL
| First Author | Sun Z | Year | 2022 |
| Journal | Neuron | Volume | 110 |
| Issue | 19 | Pages | 3106-3120.e7 |
| PubMed ID | 35961320 | Mgi Jnum | J:329489 |
| Mgi Id | MGI:7335903 | Doi | 10.1016/j.neuron.2022.07.015 |
| Citation | Sun Z, et al. (2022) Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling. Neuron |
| abstractText | Breakdown of the blood-central nervous system barrier (BCNSB) is a hallmark of many neuroinflammatory disorders, such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we show that endothelial-to-mesenchymal transition (EndoMT) occurs in the CNS before the onset of clinical symptoms and plays a major role in the breakdown of BCNSB function. EndoMT can be induced by an IL-1beta-stimulated signaling pathway in which activation of the small GTPase ADP ribosylation factor 6 (ARF6) leads to crosstalk with the activin receptor-like kinase (ALK)-SMAD1/5 pathway. Inhibiting the activation of ARF6 both prevents and reverses EndoMT, stabilizes BCNSB function, reduces demyelination, and attenuates symptoms even after the establishment of severe EAE, without immunocompromising the host. Pan-inhibition of ALKs also reduces disease severity in the EAE model. Therefore, multiple components of the IL-1beta-ARF6-ALK-SMAD1/5 pathway could be targeted for the treatment of a variety of neuroinflammatory disorders. |
