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System A amino acid transporters regulate
glutamine uptake and attenuate antibodymediated arthritis
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Bruno Raposo1,
Daniëlle Vaartjes1,
Emma Ahlqvist2,
Kutty-Selva Nandakumar1 and
Rikard Holmdahl1,3,*
Article first published online: 5 OCT 2015
DOI: 10.1111/imm.12531
© 2015 John Wiley & Sons Ltd
Issue
Immunology
Volume 146, Issue 4, (/doi/10.1111/imm.2015.146.issue-4/issuetoc) pages 607–617, December 2015
(http://www.altmetric.com/details.php?
domain=onlinelibrary.wiley.com&citation_id=4489249)
Additional Information
How to Cite
Raposo, B., Vaartjes, D., Ahlqvist, E., Nandakumar, K.-S. and Holmdahl, R. (2015), System A amino acid
transporters regulate glutamine uptake and attenuate antibody-mediated arthritis. Immunology, 146: 607–
617. doi: 10.1111/imm.12531
Author Information
1
Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics,
Karolinska Institutet, Stockholm, Sweden
2
Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital of Malmö,
Malmö, Sweden
3
Section for Medical Inflammation Research, Southern Medical University, Guangzhou, China
*
Correspondence: R. Holmdahl, Section for Medical Inflammation Research, Department of Medical
Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, 171 77 Stockholm, Sweden. Email:
[email protected] (mailto:[email protected])
Senior author: Rikard Holmdahl
Publication History
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Issue published online: 11 NOV 2015
Article first published online: 5 OCT 2015
Accepted manuscript online: 8 SEP 2015 05:16AM EST
Manuscript Accepted: 2 SEP 2015
Manuscript Revised: 31 AUG 2015
Manuscript Received: 1 JUL 2015
Funded by
Konung Gustaf V:s 80-årsfond. Grant Number: SGI2014-0009
Swedish Strategic Science Foundation. Grant Number: RB13-0156
Swedish Research Council. Grant Number: 521-2010-2894
EU IMI project BeTheCure. Grant Number: IMI-115142
Knut and Alice Wallenberg Foundation. Grant Number: KAW 2010.0148
Osteoimmune. Grant Number: EU FP7-MC-ITN-289150
Swedish Rheumatism Association. Grant Number: R-477621
Abstract
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Keywords:
amino acid transporter; arthritis; glutamine; 2-(methylamino)isobutyric acid; sodium-coupled neutral
Summary
Proliferation of rapidly dividing bone marrow-derived cells is strongly dependent on the availability of free glutamine, whose uptake is
mediated through different amino acid transporters. The sodium-coupled neutral amino acid transporter (SNAT) family was previously
reported to be associated with the development of collagen-induced arthritis in mice. Here, we tested the hypothesis whether impairment of
SNAT proteins influences immune cell function and in turn alters arthritis development. The 2-(methylamino)isobutyric acid (MeAIB), a
SNAT-specific substrate, was used to modulate the function of SNAT proteins. We demonstrate that glutamine uptake by murine naive
lymphocytes, and consequent cell proliferation, is strongly associated with system A transporters. Physiological impairment of SNAT
proteins reduced the antibody-initiated effector phase of arthritis, mainly by affecting the levels of circulating monocytes and neutrophils.
MeAIB was also shown to affect the proliferation of immortalized cells, through trans-inhibition of SNAT proteins. Based on our
observations, we conclude that SNAT proteins regulate the initial stages of lymphocyte activation by regulating glutamine uptake, and that
the effector phase of arthritis can be affected by non-metabolized SNAT substrates. Most probably, metabolically active cells within both the
adaptive and the innate immune systems are regulated by SNAT proteins and play a role in modifying arthritis development.
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