Background: Extracellular newly identified RAGE-binding protein (EN-RAGE) is a ligand of the receptor for advanced glycation endproducts (RAGE) and has been termed S100A12. The ligation of EN-RAGE with RAGE on the endothelium, mononuclear phagocytes and lymphocytes triggers cellular activation with the generation of the key proinflammatory mediators interleukin (IL)-1β and tumour necrosis factor (TNF)-α. Objectives: The aim of this study was to investigate the presence of RAGE and EN-RAGE, their spatial localization and their coexpression in leprosy lesions. Methods: Immunohistochemistry and confocal laser scanning microscopy were used to evaluate the expression of RAGE and EN-RAGE in leprosy. By enzyme-linked immunosorbent assay, RAGE and EN-RAGE were detected in the serum. Results: (1) In the multibacillary (MB) and paucibacillary (PB) groups, the level of RAGE production was significantly higher than in patients with atypical mycobacterial infection or sarcoidosis (P < 0.01). In the MB group, the production of RAGE was higher than in the PB group (P < 0.01), and it was higher in patients without the lepra reaction than in patients with the lepra reaction (P < 0.05). (2) In MB, PB and atypical mycobacterial infection, the level of EN-RAGE production was significantly higher than in sarcoidosis (P < 0.01). (3) In the confocal laser scanning microscopic examination, the RAGE and EN-RAGE proteins were detected in lepromatous leprosy. These proteins are spatially colocalized along the cell surface, which is in agreement with their receptor-ligand interaction. (4) A comparable amount of EN-RAGE was detected in the serum of the MB and PB groups. Patients with the reaction showed a higher level of EN-RAGE than patients without the reaction in leprosy. Conclusions: Our data suggest that in leprosy, RAGE and EN-RAGE may be involved in the proinflammatory process rather than the antimycobacterial activity, especially during the lepra reaction. The blockade of the interaction of RAGE and EN-RAGE at the early stage of the inflammatory process may minimize the inflammatory response and consequent tissue damage or the sequelae of leprosy.
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