TY - JOUR
T1 - Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils
AU - Riffelmacher, Thomas
AU - Giles, Daniel A.
AU - Zahner, Sonja
AU - Dicker, Martina
AU - Andreyev, Alexander Y.
AU - McArdle, Sara
AU - Perez-Jeldres, Tamara
AU - van der Gracht, Esmé
AU - Murray, Mallory Paynich
AU - Hartmann, Nadine
AU - Tumanov, Alexei V.
AU - Kronenberg, Mitchell
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
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U2 - 10.1038/s41385-021-00378-7
DO - 10.1038/s41385-021-00378-7
M3 - Article
C2 - 33568785
AN - SCOPUS:85100986114
SN - 1933-0219
VL - 14
SP - 679
EP - 690
JO - Mucosal Immunology
JF - Mucosal Immunology
IS - 3
ER -