Arginine Transport via Cationic Amino Acid Transporter 2 Plays a Critical Regulatory Role in Classical or Alternative Activation of Macrophages

Andrée Yeramian,Manuel Modolell,Antonio Celada,Lorena Martin,Concepció Soler,Neus Serrat,Manuel Palacín,Carol Mcleod,Joan Bertran,Luis Arpa,Jorge Lloberas

doi:10.4049/jimmunol.176.10.5918

Abstract

Arginine is processed by macrophages in response to the cytokines to which these cells are exposed. Th1-type cytokines induce NO synthase 2, which metabolizes arginine into nitrites, while the Th2-type cytokines produce arginase, which converts arginine into polyamines and proline. Activation of bone marrow-derived macrophages by these two types of cytokines increases L-arginine transport only through the y(+) system. Analysis of the expression of the genes involved in this system showed that Slc7A1, encoding cationic amino acid transporters (CAT)1, is constitutively expressed and is not modified by activating agents, while Slc7A2, encoding CAT2, is induced during both classical and alternative activation. Macrophages from Slc7A2 knockout mice showed a decrease in L-arginine transport in response to the two kinds of cytokines. However, while NO synthase 2 and arginase expression were unmodified in these cells, the catabolism of arginine was impaired by both pathways, producing smaller amounts of nitrites and also of polyamines and proline. In addition, the induction of Slc7A2 expression was independent of the arginine available and of the enzymes that metabolize it. In conclusion, the increased arginine transport mediated by activators is strongly regulated by CAT2 expression, which could limit the function of macrophages.

Highlights

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Because arginine is required for macrophage metabolism, in this study we examined whether M1 and M2 activation modulates the transport of this amino acid
Stimulation of L-arginine transport by only Th1-type inductors has been reported in several macrophage populations, including murine peritoneal [14, 25,26,27], rat alveolar [28], human monocyte derived [27], and the murine cell lines J774 (27, 29 –31) and RAW264 [32]

Summary

Abbreviations used in this paper

NOS, NO synthase; CAT, cationic amino acid transporter; KO, knockout; nor-NOHA, Nw-hydroxy-nor-L-arginine. The functional significance of arginine transporters was demonstrated in macrophages, in which NOS2-mediated NO synthesis largely depends on the extracellular supply of L-arginine (6 – 8). Depending on the cell type, a number of transport activities may be induced [9]. The first three members transport cationic L-amino acids, while the function of CAT-4 is not known. The hetero(di)meric amino acid transporter family comprises seven proteins, whose genes are SLC7A5 to SLC7A11; only yϩLAT2 (SLC7A6), yϩLAT1 (SLC7A7), and boϩAT (SLC7A9) transport cationic amino acids [9]. The B0,ϩAT transporter (SLC6A14), belonging to the SLC6 family, transports arginine, but in a sodium- and chloride-dependent fashion [10]. Which is a limiting factor that regulates the catabolism of arginine and the production of NO and polyamines

Materials and Methods

Results

Discussion