Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 69, Issue 11, Pages 1116-1129Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e3181f971e4
Keywords
Brain; Cerebral palsy; Cytokines; Interleukin 1; Matrix metalloproteinase; Perinatal white matter injury
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Funding
- FNRS
- CIHR, FRSQ, Foundation of Stars
- Centre des Neurosciences de l'Universite de Sherbrooke (Canada)
- Centre Hospitalier Universitaire Brugmann, Brussels (Belgium)
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A preclinical model showed a direct role of the interleukin 1 (IL-1) system in the pathogenesis of perinatal brain damage, but evidence linking these findings to human white matter damage (WMD) requires confirmation in human cases. We analyzed the IL-1 beta system using immunohistochemistry to characterize the expression of IL-1 receptors (IL-1R1 and IL-1R2), IL-1R antagonist (IL-1Ra), and induction of downstream effectors in 9 human brains with WMD. Interleukin 1 beta overexpression was associated with IL-1R1 and IL-1R2 immunoreactivity in areas with WMD; immunolabeling for both was detected on astrocytes and microglia/macrophages. There was no immunoreactivity for these receptors in nondamaged white matter in the same brains. Interleukin-1Ra expression was significantly less upregulated than that of IL-1 beta. This IL-1 beta/IL-1Ra imbalance was particularly pronounced in the brains of very preterm versus nearterm infants. We additionally found overexpression of matrix metalloproteinase 9 (MMP-9) in WMD areas. The MMP-9 colocalized with IL-1 beta in microglia/macrophages in affected cerebral areas. These data indicate that there is activation and proinflammatory orientation of the IL-1 system with downstream induction of MMP-9 in perinatal WMD. Because both of these mediators are known to be involved in neural cell injury, we infer that IL-1 pathway activation has a deleterious role in the pathophysiology of WMD in human neonates.
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