title: Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo.
abstract: Arginase 1, an enzyme induced by Th2 cytokines, is a hallmark of alternatively activated macrophages and is responsible for the hydrolysis of L-arginine into ornithine, the building block for the production of polyamines. Upregulation of arginase 1 has been observed in a variety of diseases, but the mechanisms by which arginase contributes to pathology are not well understood. We reveal here a unique role for arginase 1 in the pathogenesis of nonhealing leishmaniasis, a prototype Th2 disease, and demonstrate that the activity of this enzyme promotes pathology and uncontrolled growth of Leishmania parasites in vivo. Inhibition of arginase activity during the course of infection has a clear therapeutic effect, as evidenced by markedly reduced pathology and efficient control of parasite replication. Despite the clear amelioration of the disease, this treatment does not alter the Th2 response. To address the underlying mechanisms, the arginase-induced L-arginine catabolism was investigated and the results demonstrate that arginase regulates parasite growth directly by affecting the polyamine synthesis in macrophages.
authors.affiliation: Department of Immunology, Faculty of Medicine, Imperial College London, UK.
authors.forename: Pascale
authors.initials: P
authors.lastname: Kropf
authors.forename: José M
authors.initials: JM
authors.lastname: Fuentes
authors.forename: Eva
authors.initials: E
authors.lastname: Fähnrich
authors.forename: Luis
authors.initials: L
authors.lastname: Arpa
authors.forename: Shanthi
authors.initials: S
authors.lastname: Herath
authors.forename: Verena
authors.initials: V
authors.lastname: Weber
authors.forename: Germán
authors.initials: G
authors.lastname: Soler
authors.forename: Antonio
authors.initials: A
authors.lastname: Celada
authors.forename: Manuel
authors.initials: M
authors.lastname: Modolell
authors.forename: Ingrid
authors.initials: I
authors.lastname: Müller
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D001120:Arginine / Q000378:metabolism; D001854:Bone Marrow Cells; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018320:Leishmania major / Q000201:enzymology / Q000254:growth & development*; D016773:Leishmaniasis, Cutaneous / Q000201:enzymology* / Q000469:parasitology / Q000628:therapy; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011073:Polyamines / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; D011073:Polyamines; D012333:RNA, Messenger; D001120:Arginine; D001119:Arginase