NO pathways and antimicrobial activity.

 

 

Figure 1. NO pathways and antimicrobial activity.
(a) Regulation and function of inducible nitric oxide synthase, arginase and related pathways in mouse macrophages. The activity of iNOS is regulated by cytokines and microbial products (such as LPS), which affect the uptake of l-arginine (l-Arg) by cationic amino acid transporters (CAT), the synthesis of cofactors (such as BH₄ by GTP cyclohydrolase I (GTP-CH I)), the expression of iNOS mRNA and protein, the enzymatic recycling of citrulline to arginine and the depletion of arginine by arginase. Polyamines (putrescine, spermidin, spermin), products of the arginase?ODC pathway, act as immunosuppressants and can further downregulate the production of NO. A high arginase activity in the absence of iNOS can also be associated with tissue fibrosis resulting from the increased synthesis of proline via the arginase?OAT pathway⁹⁸, which is required for collagen synthesis (for example, by fibroblasts)⁶. AL, argininosuccinate lyase; AS, argininosuccinate synthetase; MIF, macrophage migration inhibitory factor; ODC, ornithine decarboxylase; OAT, ornithine aminotransferase. (b) Mechanisms of antimicrobial activity of the l-arginine?iNOS pathway. The antimicrobial activity of iNOS, which is found both in the cytosol as well as an endosomal compartment (nitroxosomes) of macrophages², can result from (A) NO radicals or S-nitrosothiols (SNO) or from peroxynitrite (ONOO^-) formed by the reaction of

NO with O₂^- generated by the NADPH oxidase of the host cell (B) or produced within the microbe itself (C). On the other hand, iNOS-dependent killing of parasites by macrophages can also be a consequence of the depletion of arginine (D?G). For certain strains of Leishmania it was shown that l-hydroxyarginine (LOHA) can inhibit the arginase activity in the macrophage and/or parasite and thereby promote parasite killing (D). Arginine is required for the synthesis of polyamines and DNA in Leishmania and African trypanosomes by the ornithine decarboxylase (ODC) pathway (E) and in T. cruzi via the arginine decarboxylase (ADC) pathway (F); in T. cruzi, which has its own constitutive NOS, it is also used for the synthesis of NO, which acts as an inhibitor of apoptosis and an additional parasite survival factor (G).