Arginase I, polyamine and prostaglandin E2 pathways suppress the inflammatory response and contribute to diffuse cutaneous leishmaniasis

Diffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of tegumentary leishmaniasis. The molecular mechanisms underlying DCL pathogenesis remain unclear, and there is no efficient treatment available. This study investigated the systemic and in situ expression of the inflammatory response that might contribute to suppression in DCL. The plasma levels of arginase, ODC, TGF-β and PGE2 were higher in DCL patients, than those from LCL patients or endemic control. In situ transcriptomic analyses reinforced the association between arginase expression and enzymes involved in prostaglandin and polyamine synthesis. Immunohistochemistry confirmed that arginase I, ODC and cyclooxygenase2 expression was higher in DCL than in LCL lesions. Inhibition of arginase or ODC abrogates L. amazonensis replication in infected human macrophages. Our data implicate arginase I, ODC, PGE2 and TGF-β in the failure to mount an efficient immune response and suggest perspectives in the development of new strategies for therapeutic intervention for DCL patient