Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils

Thomas Riffelmacher, Daniel A. Giles, Sonja Zahner, Martina Dicker, Alexander Y. Andreyev, Sara McArdle, Tamara Perez-Jeldres, Esmé van der Gracht, Mallory Paynich Murray, Nadine Hartmann, Alexei V. Tumanov, Mitchell Kronenberg

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)679-690
Number of pages12
JournalMucosal Immunology
Issue number3
StatePublished - May 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


Dive into the research topics of 'Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils'. Together they form a unique fingerprint.

Cite this