System A amino acid transporters regulate glutamine uptake and attenuate antibody-mediated arthritis.
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.
Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Bruno
http://orcid.org/0000-0003-3918-4882
B
Raposo
Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Daniëlle
D
Vaartjes
Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital of Malmö, Malmö, Sweden.
Emma
E
Ahlqvist
Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Kutty-Selva
KS
Nandakumar
Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Section for Medical Inflammation Research, Southern Medical University, Guangzhou, China.
Rikard
R
Holmdahl
D026924:Amino Acid Transport System A / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000009:adverse effects* / Q000276:immunology; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D003094:Collagen / Q000276:immunology; D004195:Disease Models, Animal; D005973:Glutamine / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
D026924:Amino Acid Transport System A; D000906:Antibodies; C432411:Slc38a1 protein, mouse; C498798:Slc38a2 protein, mouse; D005973:Glutamine; D009569:Nitric Oxide; D003094:Collagen; D012964:Sodium
2-(methylamino)isobutyric acid; amino acid transporter; arthritis; glutamine; sodium-coupled neutral amino acid transporter