Fig. 2.

Mammalian arginine metabolism pathways and M1 and M2 macrophage polarization. Arginine metabolism can be derived via NOS or arginase. NOS, which is expressed in M1 macrophages, causes arginine metabolism to release NO and citrulline, and M2 macrophages synthesize arginase, which causes arginine metabolism to release ornithine and urea. Downstream pathways of ornithine include putrescine, spermidine, and spermine, which hydrolyze products of ODC, SRM, and spermine synthase, respectively. Spermine can be resynthesized to spermidine by SMOX. As shown in the figure, putrescine and spermine downregulate the polarization of the M1 macrophages. Spermidine upregulates M1 macrophage polarization. In the case of M2 macrophage polarization, spermidine and spermine have inhibitor and enhancer effects, respectively. M1 macrophages increase NOS, but M2 macrophages upregulate arginase and ODC. Both arginine metabolic pathways arrest each other. Enzymes are shown by blue boxes and metabolites by yellow boxes, respectively. NOS, nitric oxide synthase; NO, nitric oxide; ODC, ornithine decarboxylase; SRM, spermidine synthase; SMOX, spermine oxidase