Arginine: master and commander in innate immune responses

The activation of macrophages through Toll-like receptor (TLR) signaling pathways is a major component of innate immune responses to infection. Because the production of nitric oxide (NO) from arginine by the inducible isoform of NO synthase (iNOS) in activated macrophages is essential for host defense against many pathogens, arginine availability is a critical determinant of resistance to infection. Thus, induction of the arginine catabolic enzyme arginase is exploited by some pathogens as a means of immune evasion. Details of this mechanism are revealed by studies that demonstrate that mycobacteria use a component of the TLR pathway to induce the type I isoform of arginase in macrophages through an autocrine-paracrine mechanism that involves macrophage-produced cytokines. Separate studies show that, in addition to inhibiting NO synthesis by substrate limitation, reducing the availability of arginine simply by nutrient deprivation can blunt the innate immune response by impairing a specific mitogen-activated protein kinase (MAPK) pathway downstream of TLR4. These findings illustrate the growing complexity of the roles of arginine as an enzyme substrate and also as a regulatory molecule in signal transduction pathways in immune cells.