Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils
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 mou...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2021
|
| _version_ | 1797066147969892352 |
|---|---|
| author | Riffelmacher, T Giles, DA Zahner, S Dicker, M Andreyev, AY McArdle, S Perez-Jeldres, T van der Gracht, E Murray, MP Hartmann, N Tumanov, AV Kronenberg, M |
| author_facet | Riffelmacher, T Giles, DA Zahner, S Dicker, M Andreyev, AY McArdle, S Perez-Jeldres, T van der Gracht, E Murray, MP Hartmann, N Tumanov, AV Kronenberg, M |
| author_sort | Riffelmacher, T |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:38:15Z |
| format | Journal article |
| id | oxford-uuid:47025836-9904-482e-8426-3b8d9a5ae1cf |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:38:15Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:47025836-9904-482e-8426-3b8d9a5ae1cf2022-03-26T15:17:23ZMetabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophilsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:47025836-9904-482e-8426-3b8d9a5ae1cfEnglishSymplectic ElementsSpringer Nature2021Riffelmacher, TGiles, DAZahner, SDicker, MAndreyev, AYMcArdle, SPerez-Jeldres, Tvan der Gracht, EMurray, MPHartmann, NTumanov, AVKronenberg, MInflammatory 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. |
| spellingShingle | Riffelmacher, T Giles, DA Zahner, S Dicker, M Andreyev, AY McArdle, S Perez-Jeldres, T van der Gracht, E Murray, MP Hartmann, N Tumanov, AV Kronenberg, M Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils |
| title | Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils |
| title_full | Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils |
| title_fullStr | Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils |
| title_full_unstemmed | Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils |
| title_short | Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils |
| title_sort | metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils |
| work_keys_str_mv | AT riffelmachert metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT gilesda metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT zahners metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT dickerm metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT andreyevay metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT mcardles metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT perezjeldrest metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT vandergrachte metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT murraymp metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT hartmannn metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT tumanovav metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils AT kronenbergm metabolicactivationandcolitispathogenesisispreventedbylymphotoxinbreceptorexpressioninneutrophils |