Systemic inflammation sensitizes the neonatal brain to excitotoxicity through a pro-/anti-inflammatory imbalance: key role of TNFalpha pathway and protection by etanercept.
Systemic inflammation sensitizes the perinatal brain to an ischemic/excitotoxic insult but the mechanisms are poorly understood. We hypothesized that the mechanisms involve an imbalance between pro- and anti-inflammatory factors. A well characterized mouse model where a systemic injection of IL-1beta during the first five postnatal days (inflammatory insult) is combined with an intracerebral injection of the glutamatergic analogue ibotenate (excitotoxic insult) at postnatal day 5 was used. Following the inflammatory insult alone, there was a transient induction of IL-1beta and TNFalpha, compared with controls measured by quantitative PCR, ELISA, and Western blot. Following the combined inflammatory and excitotoxic insult, there was an induction of IL-1beta, TNFalpha, and IL-6 but not of IL-10 and TNFR1, indicating an altered pro-/anti-inflammatory balance after IL-1beta sensitized lesion. We then tested the hypothesis that the TNFalpha pathway plays a key role in the sensitization and insult using TNFalpha blockade (etanercept) and TNFalpha(-/-) mice. Etanercept given before the insult did not affect brain damage, but genetic deletion of TNFalpha or TNFalpha blockade by etanercept given after the combined inflammatory and excitotoxic insult reduced brain damage by 50%. We suggest this protective effect was centrally mediated, since systemic TNFalpha administration in the presence of an intact blood-brain barrier did not aggravate the damage and etanercept almost abolished cerebral TNFalpha production. In summary, sensitization was, at least partly, mediated by an imbalance between pro- and anti-inflammatory cytokines. Cerebral TNFalpha played a key role in mediating brain damage after the combined inflammatory and excitatory insult.
Inserm, U676, Paris, France.
Ulrika
U
Adén
Géraldine
G
Favrais
Frank
F
Plaisant
Max
M
Winerdal
Ursula
U
Felderhoff-Mueser
Jon
J
Lampa
Vincent
V
Lelièvre
Pierre
P
Gressens
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D005260:Female; D007051:Ibotenic Acid; D007074:Immunoglobulin G / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D016753:Interleukin-10 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood / Q000494:pharmacology; D007376:Interleukin-2 / Q000097:blood; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008840:Microfilament Proteins; D037121:Plant Lectins / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; C045475:Griffonia simplicifolia lectins; D007074:Immunoglobulin G; D007155:Immunologic Factors; D053583:Interleukin-1beta; D007376:Interleukin-2; D008840:Microfilament Proteins; D037121:Plant Lectins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007051:Ibotenic Acid; D017493:Leukocyte Common Antigens; D053148:Caspase 3; D000068800:Etanercept