Proteoglycan 4 Reduces Neuroinflammation and Protects the Blood–Brain Barrier after Traumatic Brain Injury
| Autor: | Adam Chodobski, Gregory D. Jay, Tannin A. Schmidt, Nathalie Strazielle, Marissa Bennett, Holly A. Richendrfer, Hyung Jin Lee, Emma Morales Cestero, Joanna Szmydynger-Chodobska, Jean-François Ghersi-Egea, Steven W. Threlkeld, Andrea T. Chin |
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| Rok vydání: | 2021 |
| Předmět: |
Male
030506 rehabilitation Traumatic brain injury Inflammation blood–brain barrier Blood–brain barrier neuroinflammation 03 medical and health sciences 0302 clinical medicine Proteoglycan 4 Brain Injuries Traumatic medicine Animals Rats Long-Evans CD44 Receptor Neuroinflammation proteoglycan 4 Cell Death biology business.industry NF-kappa B Brain Original Articles medicine.disease Toll-like receptors Rats medicine.anatomical_structure Blood-Brain Barrier Models Animal biology.protein Encephalitis Proteoglycans Neurology (clinical) medicine.symptom 0305 other medical science business Neuroscience 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Journal of Neurotrauma |
| ISSN: | 1557-9042 0897-7151 |
| Popis: | Neuroinflammation and dysfunction of the blood–brain barrier (BBB) are two prominent mechanisms of secondary injury in neurotrauma. It has been suggested that Toll-like receptors (TLRs) play important roles in initiating and propagating neuroinflammation resulting from traumatic brain injury (TBI), but potential beneficial effects of targeting these receptors in TBI have not been broadly studied. Here, we investigated the effect of targeting TLRs with proteoglycan 4 (PRG4) on post-traumatic neuroinflammation and BBB function. PRG4 is a mucinous glycoprotein with strong anti-inflammatory properties, exerting its biological effects by interfering with TLR2/4 signaling. In addition, PRG4 has the ability to inhibit activation of cluster of differentiation 44 (CD44), a cell-surface glycoprotein playing an important role in inflammation. Using the controlled cortical impact model of TBI in rats, we showed a rapid and prolonged upregulation of message for TLR2/4 and CD44 in the injured cortex. In the in vitro model of the BBB, recombinant human PRG4 (rhPRG4) crossed the endothelial monolayers through a high-capacity, saturable transport system. In rats sustaining TBI, PRG4 delivery to the brain was enhanced by post-traumatic increase in BBB permeability. rhPRG4 injected intravenously at 1 h post-TBI potently inhibited post-traumatic activation of nuclear factor kappa B and extracellular signal-regulated kinases 1/2, the two major signal transduction pathways associated with TLR2/4 and CD44, and curtailed the post-traumatic influx of monocytes. In addition, PRG4 restored normal BBB function after TBI by preventing the post-traumatic loss of tight junction protein claudin 5 and reduced neuronal death. Our observations provide support for therapeutic strategies targeting TLRs in TBI. |
| Databáze: | OpenAIRE |
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