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PMID: 18369473 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

Cationic amino acid transporter-2 regulates immunity by modulating arginase activity.

PLoS pathogens ·Vol. 4 ·No. 3 ·2008-03-14 ·Pages e1000023

Thompson RW, Pesce JT, Ramalingam T, Wilson MS, White S, Cheever AW, Ricklefs SM, Porcella SF, Li L, Ellies LG, Wynn TA

Abstract

Cationic amino acid transporters (CAT) are important regulators of NOS2 and ARG1 activity because they regulate L-arginine availability. However, their role in the development of Th1/Th2 effector functions following infection has not been investigated. Here we dissect the function of CAT2 by studying two infectious disease models characterized by the development of polarized Th1 or Th2-type responses. We show that CAT2(-/-) mice are significantly more susceptible to the Th1-inducing pathogen Toxoplasma gondii. Although T. gondii infected CAT2(-/-) mice developed stronger IFN-gamma responses, nitric oxide (NO) production was significantly impaired, which contributed to their enhanced susceptibility. In contrast, CAT2(-/-) mice infected with the Th2-inducing pathogen Schistosoma mansoni displayed no change in susceptibility to infection, although they succumbed to schistosomiasis at an accelerated rate. Granuloma formation and fibrosis, pathological features regulated by Th2 cytokines, were also exacerbated even though their Th2 response was reduced. Finally, while IL-13 blockade was highly efficacious in wild-type mice, the development of fibrosis in CAT2(-/-) mice was largely IL-13-independent. Instead, the exacerbated pathology was associated with increased arginase activity in fibroblasts and alternatively activated macrophages, both in vitro and in vivo. Thus, by controlling NOS2 and arginase activity, CAT2 functions as a potent regulator of immunity.

MeSH Terms
Animals Arginase/metabolism Cationic Amino Acid Transporter 2/physiology Cell Proliferation Cells, Cultured Disease Models, Animal Female Fibroblasts/cytology,enzymology Fibrosis/parasitology,pathology Gene Expression Gene Silencing Granuloma/parasitology,pathology Immunity Liver/metabolism,parasitology,pathology Lung/metabolism,parasitology,pathology Lung Diseases, Parasitic/metabolism,parasitology,pathology Lymph Nodes/parasitology,pathology Macrophage Activation Macrophages/enzymology,immunology Male Mice Mice, Knockout Nitric Oxide/metabolism Schistosoma mansoni/isolation & purification,pathogenicity,physiology Schistosomiasis mansoni/enzymology,genetics,immunology Th1 Cells/enzymology,immunology Th2 Cells/enzymology,immunology
Chemicals
Cationic Amino Acid Transporter 2 Nitric Oxide Arginase
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Thompson Robert W
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Pesce John T
Ramalingam Thirumalai
Wilson Mark S
White Sandy
Cheever Allen W
Ricklefs Stacy M
Porcella Stephen F
Li Lili
Ellies Lesley G
Wynn Thomas A
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Article Info
Journal
PLoS pathogens
Abbr.
PLoS Pathog
ISSN
1553-7374
DOI
10.1371/journal.ppat.1000023
Published
2008-03-14
Epub
2008-00-14
Pages
e1000023
Language
English
Region
United States
NLM ID
101238921
PMCID
PMC2265428
Subset
IM
Grants
NCI NIH HHS · K22 CA118182 · United States
Intramural NIH HHS · United States
NCI NIH HHS · CA118182 · United States
External Links
PubMed source DOI: 10.1371/journal.ppat.1000023 PMC Full Text View journal details
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