Arginase in parasitic infections: macrophage activation, immunosuppression, and intracellular signals

Abstract

A type 1 cytokine-dependent proinflammatory response inducing classically activated macrophages (CaMvarphis) is crucial for parasite control during protozoan infections but can also contribute to the development of immunopathological disease symptoms. Type 2 cytokines such as IL-4 and IL-13 antagonize CaMvarphis inducing alternatively activated macrophages (AaMvarphis) that upregulate arginase-1 expression. During several infections, induction of arginase-1-macrophages was showed to have a detrimental role by limiting CaMvarphi-dependent parasite clearance and promoting parasite proliferation. Additionally, the role of arginase-1 in T cell suppression has been explored recently. Arginase-1 can also be induced by IL-10 and transforming growth factor-beta (TGF-beta) or even directly by parasites or parasite components. Therefore, generation of alternative activation states of macrophages could limit collateral tissue damage because of excessive type 1 inflammation. However, they affect disease outcome by promoting parasite survival and proliferation. Thus, modulation of macrophage activation may be instrumental in allowing parasite persistence and long-term host survival.

Figure 1

Role of macrophage activation in parasitic infections. A type 1 cytokine-dependent proinflammatory response inducing classically activated macrophages (CaMϕs) leads to NO production and also to the synthesis of several products of NO reaction. CaMϕs are crucial for parasite control during protozoan infections but can also contribute to the development of immunopathological disease symptoms. Type 2 cytokines such as IL-4 and IL-13 antagonize CaMϕs inducing alternatively activated macrophages (AaMϕs) that upregulate arginase-1 expression. Arginase-1 can also be induced during the infection by apoptotic cells or even directly by parasites or parasite components. Arginase-1 limits CaMϕ-dependent parasite clearance promoting parasite proliferation. Additionally, arginase-1 suppresses T cell response. Therefore, generation of alternative activation states of macrophages could limit collateral tissue damage because of excessive type 1 inflammation. However, they affect disease outcome by promoting parasite survival and proliferation.

Figure 2

Role of arginase in immunosuppression. During parasitic infections, mouse macrophage-specific arginase-1 induces T cell suppression due to arginase-mediated depletion of L-arginine in the T cell environment, which leads to CD3ζ chain down-regulation. Additionally, PD-1/PD-L pathway may be also involved in the T cell suppression. Furthermore, human granulocyte arginase can also induce immunosuppression by a similar mechanism. Upon human polymorphonuclear granulocytes (PMN) cell death, arginase is liberated and high activities of this enzyme accumulate extracellularly during purulent inflammatory reactions. PMN arginase induces a profound suppression of T cell and NK cell proliferation and cytokine synthesis.