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

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.

NBS1 is required for macrophage homeostasis and functional activity in mice

“…The resulting homogenous population of cells was composed of quiescent primary macrophages that could be induced to proliferate by growth factors or that could be classically and alternatively activated by cytokines. 30 BMDMs were incubated with different proinflammatory (IFN-g and LPS), anti-inflammatory (IL-4), and proliferative stimuli (M-CSF and GM-CSF), and levels of NBS1 were determined after treatment. No significant changes in Nbs1 messenger RNA (mRNA) levels ( Figure 1A) were observed.…”

IL‐4 blocks M‐CSF‐dependent macrophage proliferation by inducing p21Waf1 in a STAT6‐dependent way

“…In alternative activation, the expression of arginase 1 is induced, together with the up-regulation of the mannose receptor and several other markers [4]. Curiously, arginine is the substrate for NOS2 and arginase 1, and the system that transports this amino acid is induced by both types of cytokines, thereby providing more arginine inside the cell [5,6].…”

A l-Lysine Transporter of High Stereoselectivity of the Amino Acid-Polyamine-Organocation (APC) Superfamily

“…In addition, sensors and transporters of amino acids in Saccharomyces cerevisiae can be considered as APC transporter homologues (8). In mammals, the APC transporters play a pivotal role in amino acid transport-related processes including redox imbalance (9), neuroadaptation (10), macrophage activation and proliferation (11), growth and survival of cancer cells (12), and primary inherited cystinuria and lysinuric protein intolerance (13)(14)(15). Various amino acid transporters including a serine transporter of the Na ϩ /Ser symporter family (16); AroPPheP, a tryptophan transporter of the aromatic amino acid transport family (17); AdiC, an arginine-agmatine transporter (18 -20); ApcT, a proton-dependent broad specificity amino acid transporter (1) of the APC superfamily; the Na ϩ -independent neutral amino acid transporter (21); and the glutamate and aspartate transporter of the excitatory amino acid transporter family (22,23) have been studied using Escherichia coli.…”