Cationic amino acid transporter 2 regulates inflammatory homeostasis in the lung

Abstract

Arginine is an amino acid that serves as a substrate for nitric oxide synthase and arginase. As such, arginine has the potential to influence diverse fundamental processes in the lung. Here we report that the arginine transport protein, cationic amino acid transporter (CAT)2, has a critical role in regulating lung inflammatory responses. Analysis of CAT2-deficient mice revealed spontaneous inflammation in the lung. Marked eosinophilia, associated with up-regulation of eotaxin-1, was present in the bronchoalveolar lavage fluid of 3-week-old CAT2-deficient mice. The eosinophilia was gradually replaced by neutrophilia in adult mice, while eotaxin-1 levels decreased and GRO-␣ levels increased. Despite the presence of activated alveolar macrophages in CAT2-deficient mice, NO production was compromised in these cells. Examination of dendritic cell activation, which can be affected by NO release, indicated increased dendritic cell activation in the lungs of CAT2-deficient mice. This process was accompanied by an increase in the number of memory T cells. Thus, our data suggest that CAT2 regulates anti-inflammatory processes in the lungs via regulation of dendritic cell activation and subsequent T cell responses.inflammation ͉ dendritic cells ͉ arginase ͉ nitric oxide

The cationic amino acid transporter 2 is induced in inflammatory lung models and regulates lung fibrosis

“…The level of systemic sensitization, as measured by OVA-specific IgG1, was comparable between wild type and CAT2-deficient mice (n = 4 experiments, data not shown). Saline-challenged CAT2-deficient mice had baseline inflammation (primarily neutrophilia) as we have previously reported [8]. In summary, our data demonstrate appropriate inflammatory responses in the lung in response to allergic stimuli.…”

Increased mitochondrial arginine metabolism supports bioenergetics in asthma

“…ARG2 is located in the mitochondria, and its higher expression and production of ornithine in asthma may CAT2-deficient mice have spontaneous eosinophilic lung inflammation (18,35). However, expression of CAT2 and CAT3 was similar in bronchial epithelial cells from asthma and control, while CAT1 was undetectable in all samples (n ≥ 3) (data not shown).…”

Macrophage Expression of Hypoxia-Inducible Factor-1α Suppresses T-Cell Function and Promotes Tumor Progression

“…Mice harboring mutations of the cationic amino acid transporter-2 (CAT2), which is essential for myeloid cell production of significant amounts of nitric oxide via iNOS, or for significant throughput through the ArgI pathway (45, 46), develop spontaneous lung inflammation at 3 weeks of age (47). One group has reported that global iNOS deficiency results in increased T cell activity (48); also of note are reports that wild type mice show an IFNγ-dependent resistance to autoimmunity, whereas iNOS null mice remain susceptible (49, 50).…”