title: Deletion of cationic amino acid transporter 2 exacerbates dextran sulfate sodium colitis and leads to an IL-17-predominant T cell response.
abstract: L-Arginine (L-Arg) is a semiessential amino acid that has altered availability in human ulcerative colitis (UC), a form of inflammatory bowel disease, and is beneficial in murine colitis induced by dextran sulfate sodium (DSS), a model with similarity to UC. We assessed the role of cationic amino acid transporter 2 (CAT2), the inducible transporter of L-Arg, in DSS colitis. Expression of CAT2 was upregulated in tissues from colitic mice and localized predominantly to colonic macrophages. CAT2-deficient (CAT2-/-) mice exposed to DSS exhibited worsening of survival, body weight loss, colon weight, and histological injury. These effects were associated with increased serum L-Arg and decreased tissue L-Arg uptake and inducible nitric oxide synthase protein expression. Clinical benefits of L-Arg supplementation in wild-type mice were lost in CAT2-/- mice. There was increased infiltration of macrophages, dendritic cells, granulocytes, and T cells in colitic CAT2-/- compared with wild-type mice. Cytokine profiling revealed increases in proinflammatory granulocyte colony-stimulating factor, macrophage inflammatory protein-1α, IL-15, and regulated and normal T cell-expressed and -secreted and a shift from an IFN-γ- to an IL-17-predominant T cell response, as well as an increase in IL-13, in tissues from colitic CAT2-/- mice. However, there were no increases in other T helper cell type 2 cytokines, nor was there a global increase in macrophage-derived proinflammatory cytokines. The increase in IL-17 derived from both CD4 and γδ T cells and was associated with colonic IL-6 expression. Thus CAT2 plays an important role in controlling inflammation and IL-17 activation in an injury model of colitis, and impaired L-Arg availability may contribute to UC pathogenesis.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Kshipra
authors.initials: K
authors.lastname: Singh
authors.forename: Lori A
authors.initials: LA
authors.lastname: Coburn
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Barry
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.forename: Brooks P
authors.initials: BP
authors.lastname: Scull
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Allaman
authors.forename: Nuruddeen D
authors.initials: ND
authors.lastname: Lewis
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rosen
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D027202:Cationic Amino Acid Transporter 2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D003092:Colitis / Q000139:chemically induced* / Q000276:immunology* / Q000503:physiopathology; D016264:Dextran Sulfate; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D027202:Cationic Amino Acid Transporter 2; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D012333:RNA, Messenger; D016264:Dextran Sulfate; D001120:Arginine
keywords: IL-17; T helper cells; arginine metabolism; colitis; macrophages