TNF Receptor 1 Promotes Early-Life Immunity and Protects against Colitis in Mice

Cell Rep. 2020 Oct 20;33(3):108275. doi: 10.1016/j.celrep.2020.108275.


Neutralization of tumor necrosis factor (TNF) represents a widely used therapeutic strategy for autoimmune diseases including inflammatory bowel disease (IBD). However, the fact that many patients with IBD are non-responsive to anti-TNF therapies suggests the need for a better understanding of TNF signaling in IBD. Here, we show that co-deletion of TNF receptor 1 (TNFR1, Tnfrsf1a) in the Il10-/- spontaneous colitis model exacerbates disease, resulting in very-early-onset inflammation after weaning. The disease can be interrupted by treatment with antibiotics. The single deletion of TNFR1 induces subclinical colonic epithelial dysfunction and mucosal immune abnormalities, including accumulation of neutrophils and depletion of B cells. During the pre-disease period (before weaning), both Tnfr1-/- and Il10-/-Tnfr1-/- animals exhibit impaired expression of pro-inflammatory cytokines compared with wild-type and Il10-/- controls, respectively. Collectively, these results demonstrate the net anti-inflammatory functions of TNF/TNFR1 signaling through the regulation of colonic immune homeostasis in early life.

Keywords: IBD; antibiotics; barrier; microbiome; mucosa; tolerance; weaning reaction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / genetics*
  • Colitis / immunology
  • Colitis / metabolism
  • Colon / pathology
  • Cytokines / metabolism
  • Dextran Sulfate / pharmacology
  • Epithelial Cells / metabolism
  • Female
  • Inflammation / pathology
  • Inflammatory Bowel Diseases / pathology
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor Inhibitors / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism


  • Cytokines
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Dextran Sulfate