Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo.
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.
Kropf
Pascale
P
Department of Immunology, Faculty of Medicine, Imperial College London, UK.
Fuentes
José M
JM
Fähnrich
Eva
E
Arpa
Luis
L
Herath
Shanthi
S
Weber
Verena
V
Soler
Germán
G
Celada
Antonio
A
Modolell
Manuel
M
Müller
Ingrid
I
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
D004791:Enzyme Inhibitors; D011073:Polyamines; D012333:RNA, Messenger; D001120:Arginine; D001119:Arginase