Riffelmacher T(#)(1)(2), Giles DA(#)(1), Zahner S(1), Dicker M(1), Andreyev AY(3), McArdle S(1), Perez-Jeldres T(1), van der Gracht E(1), Murray MP(1), Hartmann N(1), Tumanov AV(4), Kronenberg M(5)(6). Author information:
(1)La Jolla Institute for Immunology, La Jolla, CA, USA.
(2)Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
(3)Department of Pharmacology, University of California San Diego, La Jolla, CA,
(4)Department of Microbiology, Immunology and Molecular Genetics, University of
Texas Health Science Center San Antonio, San Antonio, USA.
(5)La Jolla Institute for Immunology, La Jolla, CA, USA. [Email]
(6)Division of Biological Sciences, University of California San Diego, La
Jolla, CA, USA. [Email]
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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