Journal article
Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils
- Abstract:
- Inflammatory bowel disease is characterized by an exacerbated intestinal immune response, but the critical mechanisms regulating immune activation remain incompletely understood. We previously reported that the TNF-superfamily molecule TNFSF14 (LIGHT) is required for preventing severe disease in mouse models of colitis. In addition, deletion of lymphotoxin beta receptor (LTβR), which binds LIGHT, also led to aggravated colitis pathogenesis. Here, we aimed to determine the cell type(s) requiring LTβR and the mechanism critical for exacerbation of colitis. Specific deletion of LTβR in neutrophils (LTβRΔN), but not in several other cell types, was sufficient to induce aggravated colitis and colonic neutrophil accumulation. Mechanistically, RNA-Seq analysis revealed LIGHT-induced suppression of cellular metabolism, and mitochondrial function, that was dependent on LTβR. Functional studies confirmed increased mitochondrial mass and activity, associated with excessive mitochondrial ROS production and elevated glycolysis at steady-state and during colitis. Targeting these metabolic changes rescued exacerbated disease severity. Our results demonstrate that LIGHT signals to LTβR on neutrophils to suppress metabolic activation and thereby prevents exacerbated immune pathogenesis during colitis.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 8.7MB, Terms of use)
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- Publisher copy:
- 10.1038/s41385-021-00378-7
Authors
- Publisher:
- Springer Nature
- Journal:
- Mucosal Immunology More from this journal
- Volume:
- 14
- Pages:
- 679–690
- Publication date:
- 2021-02-10
- Acceptance date:
- 2020-12-30
- DOI:
- EISSN:
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1935-3456
- Language:
-
English
- Keywords:
- Pubs id:
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1162116
- Local pid:
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pubs:1162116
- Deposit date:
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2021-02-18
Terms of use
- Copyright holder:
- Riffelmacher et al.
- Copyright date:
- 2021
- Rights statement:
- ©2021 The Authors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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