High-Mobility Group Box-1 and Its Receptors Contribute to Proinflammatory Response in the Acute Phase of Spinal Cord Injury in Rats

Study Design. To examine the localization and expression of high-mobility group box-1 (HMGB-1) protein and its receptors after rat spinal cord injury. Objective. To elucidate the contribution of HMGB-1 and its receptors as potential candidates in a specific upstream pathway to the proinflammatory response leading to a cascade of secondary tissue damage after spinal cord injury. Summary of Background Data. HMGB-1 was recently characterized as a key cytokine with a potential role in nucleosome formation and regulation of gene transcription. No studies have investigated the role of HMGB-1 in spinal cord injury. Methods. Injured thoracic spinal cord from 62 rats aged 8 to 12 weeks and spinal cord from 20 control rats were examined. HMGB-1 was localized by immunofluorescence staining, costaining with cell markers, and by immunoelectron microscopy. The expression of HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)2, and TLR4 were also examined by immunohistochemistry. Results. HMGB-1 expression appeared earlier than that of tumor necrosis factor-&agr;, interleukin (IL)-1&bgr;, and IL-6 in the spinal cord injury rats, with the HMGB-1 produced by both macrophages and neurons. HMGB-1 translocated from nucleus to cytoplasm in some neurons at an early stage after neural injury. Increased expression of HMGB-1, RAGE, and TLRs was observed after injury, and interaction of HMGB-1 with RAGE or TLRs, particularly in macrophage, was confirmed at 3 days after injury. Conclusion. Our results demonstrated an earlier onset in the expression of HMGB-1 than in tumor necrosis factor-&agr;, IL-1&bgr;, and IL-6 after spinal cord injury. The release of HMGB-1 from neurons and macrophages is mediated through the HMGB-1/RAGE or TLR pathways. HMGB-1 seems to play at least some roles in the proinflammatory cascade originating the secondary damage after the initial spinal cord injury.

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