L-arginine availability modulates local nitric oxide production and parasite killing in experimental trypanosomiasis

Nitric oxide (NO) is an important effector molecule of the immune system in eliminating numerous pathogens. Peritoneal macrophages from Trypanosoma br ucei brucei-infected mice express type II NO synthase (NOS-II), produce NO, and kill parasites in the presence of L-arginine in vitro. Nevertheless, p arasites proliferate in the vicinity of these macrophages in vivo. The pres ent study shows that L-arginine availability modulates NO production. Trypa nosomes use L-arginine for polyamine synthesis, required for DNA and trypan othione synthesis. Moreover, arginase activity is up-regulated in macrophag es from infected mice from the first days of infection. Arginase competes w ith NOS-II for their common substrate, L-arginine. In vitro, arginase inhib itors decreased urea production, increased macrophage nitrite production, a nd restored trypanosome killing. In vivo, a dramatic decrease in L-arginine concentration was observed in plasma from infected mice. In situ restorati on of NO production and trypanosome killing were observed when excess L-arg inine, but not D-arginine or L-arginine plus N-omega-nitro-L-arginine (a NO S inhibitor), was injected into the peritoneum of infected mice. These data indicate the role of L-arginine depletion, induced by arginase and parasit es, in modulating the L-arginine-NO pathway under pathophysiological condit ions.