Baier, Julia and Gaensbauer, Maximilian and Giessler, Claudia and Arnold, Harald and Muske, Mercedes and Schleicher, Ulrike and Lukassen, Soeren and Ekici, Arif and Rauh, Manfred and Daniel, Christoph and Ha Rtmann, Arndt and Schmid, Benjamin and Tripal, Philipp and Dettmer, Katja and Oefner, Peter J. and Atreya, Raja and Wirtz, Stefan and Bogdan, Christian and Mattner, Jochen (2020) Arginase impedes the resolution of colitis by altering the microbiome and metabolome. JOURNAL OF CLINICAL INVESTIGATION, 130 (11). pp. 5703-5720. ISSN 0021-9738, 1558-8238
Full text not available from this repository. (Request a copy)Abstract
Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4/IL-13(-) and intestinal microbiota-dependent manner. Tie2-Cre Arg1(fl/fl) mice lacking Argl in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing (Arg1(fl/fl)) littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells, and an accumulation of intraluminal polyamines that promote epithelial healing. The proresolving effect of Argl deletion was reduced by an L-arginine-free diet, but rescued by simultaneous deletion of other L-arginine-metabolizing enzymes, such as Arg2 or Nos2, demonstrating that protection from colitis requires L-arginine. Fecal microbiota transfers from Tie2-Cre Arg1(fl/fl) mice into WT recipients ameliorated intestinal inflammation, while transfers from WT littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of L-arginine as well as altered intestinal microbiota and metabolic products accounts for the accelerated resolution from colitis in the absence of Arg1. Consequently, L-arginine metabolism may serve as a target for clinical intervention in IBD patients.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INFLAMMATORY-BOWEL-DISEASE; INNATE LYMPHOID-CELLS; NITRIC-OXIDE SYNTHASE; IMMUNE-RESPONSES; C5A RECEPTOR; ENDOTHELIAL DYSFUNCTION; INTESTINAL INFLAMMATION; ARGININE METABOLISM; ULCERATIVE-COLITIS; MACROPHAGES; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Mar 2021 10:00 |
| Last Modified: | 08 Mar 2021 10:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43420 |
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