Proinflammatory Orientation of the Interleukin 1 System and Downstream Induction of Matrix Metalloproteinase 9 in the Pathophysiology of Human Perinatal White Matter Damage

• Published in: Journal of neuropathology and experimental neurology 2010-11, Vol.69 (11), p.1116-1129
• Main Authors: Girard, Sylvie, Sébire, Guillaume, Kadhim, Hazim
• Format: Article
• Language: English
• Subjects: Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Apoptosis - physiology; Biological and medical sciences; Brain Injuries - enzymology; Brain Injuries - pathology; Brain Injuries - physiopathology; Female; Gene Expression Regulation, Enzymologic - physiology; Glial Fibrillary Acidic Protein - metabolism; Humans; Infant; Infant, Newborn; Injuries of the nervous system and the skull. Diseases due to physical agents; Interleukin 1 Receptor Antagonist Protein - metabolism; Interleukin-1 - metabolism; Male; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Nerve Fibers, Myelinated - pathology; Neurology; Signal Transduction - physiology; Traumas. Diseases due to physical agents; Tumors of the nervous system. Phacomatoses
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/NEN.0b013e3181f971e4

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-1β 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 1β 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-1β. This IL-1β/IL-1Ra imbalance was particularly pronounced in the brains of very preterm versus near-term infants. We additionally found overexpression of matrix metalloproteinase 9 (MMP-9) in WMD areas. The MMP-9 colocalized with IL-1β 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.