Tumor necrosis factor receptor-1 is essential for LPS-induced sensitization and tolerance to oxygen-glucose deprivation in murine neonatal organotypic hippocampal slices.
Inflammation and ischemia have a synergistic damaging effect in the immature brain. The role of tumor necrosis factor (TNF) receptors 1 and 2 in lipopolysaccharide (LPS)-induced sensitization and tolerance to oxygen-glucose deprivation (OGD) was evaluated in neonatal murine hippocampal organotypic slices. Hippocampal slices from balb/c, C57BL/6 TNFR1(-/-), TNFR2(-/-), and wild-type (WT) mice obtained at P6 were grown in vitro for 9 days. Preexposure to LPS immediately before OGD increased propidium iodide-determined cell death in regions CA1, CA3, and dentate gyrus from 4 up to 48 h after OGD (P<0.001). Extending the time interval between LPS exposure and OGD to 72 h resulted in tolerance, that is reduced neuronal cell death after OGD (P<0.05). Slices from TNFR1(-/-) mice showed neither LPS-induced sensitization nor LPS-induced tolerance to OGD, whereas both effects were present in slices from TNFR2(-/-) and WT mice. Cytokine secretion (TNFalpha and interleukin-6) during LPS exposure was decreased in TNFR1(-/-) slices and increased in TNFR2(-/-) as compared with WT slices. We conclude that LPS induces sensitization or tolerance to OGD depending on the time interval between exposure to LPS and OGD in murine hippocampal slice cultures. Both paradigms are dependent on signaling through TNFR1.
Markus
Tina
T
Department of Pediatrics, Lund University, Lund, Sweden. Tina.Markus@med.lu.se
Cronberg
Tobias
T
Cilio
Corrado
C
Pronk
Cornelis
C
Wieloch
Tadeusz
T
Ley
David
D
D000818:Animals; D000831:Animals, Newborn; D005947:Glucose / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques
D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D005947:Glucose; D010100:Oxygen