Retinal neuroinflammatory induced neuronal degeneration - Role of toll-like receptor-4 and relationship with gliosis
| Autor: | Fredrik Ghosh, Karin Arnér, Ulrikke Voss, Linnéa Taylor, Hodan Abdshill |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Retinal degeneration Lipopolysaccharides Proteomics Programmed cell death Cell Survival Swine Galectin 3 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Glutamate-Ammonia Ligase Transforming Growth Factor beta Glial Fibrillary Acidic Protein medicine Animals Gliosis Cells Cultured Inflammation Retina Glial fibrillary acidic protein biology Retinal Degeneration Retinal medicine.disease Molecular biology Sensory Systems Toll-Like Receptor 4 Ophthalmology Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry Nerve Degeneration biology.protein TLR4 Cytokines medicine.symptom 030217 neurology & neurosurgery Retinal Neurons |
| Zdroj: | Experimental eye research. 169 |
| ISSN: | 1096-0007 |
| Popis: | The purpose of this study was to explore retina-intrinsic neuroinflammatory reactions, effects on neuronal survival, relationship with classic gliosis, and possible role of the toll-like receptor 4 (TLR4). To isolate the adult retina from the systemic immune system, a previously described large animal explant culture model was used in which full-thickness porcine retinal sheets can be kept in vitro for extended time periods. Explants were kept for 5 days in vitro (DIV) and were treated with either; lipopolysaccharide (LPS), a Toll-like receptor-4 (TLR4) inhibitor (CLI-095), LPS + CLI-095, or solvent vehicle throughout the culture period after which retinal sections were examined with hematoxylin and eosin staining and extensive immunohistochemistry. In addition, the culture medium of all explants was assayed for a panel of cytokines at 2 and 5DIV. Compared with in vivo controls, vehicle controls (CT) as well as CLI-095 explants displayed moderate reduction of total thickness and number of retinal neurons with upregulation of glial fibrillary acidic protein (GFAP) throughout the Muller cells. In contrast, LPS and LPS + CLI-095 treated counterparts showed extensive overall thinning with widespread neuronal degeneration but only minimal signs of classical Muller cell gliosis (limited upregulation of GFAP and no downregulation of glutamine synthetase (GS). These specimens also displayed a significantly increased expression of galectin-3 and TGF-beta activated kinase 1 (TAK1). Multiplex proteomic analysis of culture medium at 2DIV revealed elevated levels of IL-1β, IL-6, IL-4 and IL-12 in LPS-treated explants compared to CLI-095 and CT counterparts. LPS stimulation of the isolated adult retina results in substantial neuronal cell death despite only minimal signs of gliosis indicating a retina-intrinsic neuroinflammatory response directly related to the degenerative process. This response is characterized by early upregulation of several inflammatory related cytokines with subsequent upregulation of Galectin-3, TLR4 and TAK1. Pharmacological block of TLR4 does not attenuate neuronal loss indicating that LPS induced retinal degeneration is mediated by TLR4 independent neuroinflammatory pathways. |
| Databáze: | OpenAIRE |
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