Cationic Amino Acid Transporter-2 Regulates Immunity by Modulating Arginase Activity

PLoS Pathogens

Allen W. Cheever¹  Lili Li²  Stephen F. Porcella³  Stacy M. Ricklefs³  John T. Pesce⁴  Sandy White⁴  Mark S. Wilson⁴  Thomas A. Wynn⁴  Thirumalai Ramalingam⁴  Robert W. Thompson⁴  Lesley G. Ellies⁵ 

[1] Biomedical Research Institute, Rockville, Maryland, United States of America;Centocor Inc., Malvern, Pennsylvania, United States of America;Genomics Unit, Research Technologies Section, Rocky Mountain Laboratories, Hamilton, Montana, United States of America;Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Moores UCSD Cancer Center, University of California San Diego, La Jolla, California United States of America

关键词: Fibroblasts;    Macrophages;    Granulomas;    Schistosoma mansoni;    Cytokines;    Fibrosis;    Mouse models;    Toxoplasma gondii;   

DOI  :  10.1371/journal.ppat.1000023

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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-γ 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.

【 授权许可】

CC BY