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

• Published in: Cell reports (Cambridge) Vol. 33; no. 3; p. 108275
• Main Authors: Liu, Cambrian Y., Tam, Sharon S., Huang, Ying, Dubé, Philip E., Alhosh, Rabea, Girish, Nandini, Punit, Shivesh, Nataneli, Shirin, Li, Fan, Bender, Jeffrey M., Washington, M. Kay, Polk, D. Brent
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.10.2020; Elsevier
• Subjects: antibiotics; barrier; IBD; microbiome; mucosa; tolerance; weaning reaction; barrier; IBD; microbiome; antibiotics; mucosa; weaning reaction; tolerance
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •Il10−/−Tnfr1−/− mice exhibit severe colitis beginning shortly after weaning•Colitis is dependent on the microbiome but is not taxa specific•Tnfr1−/− mice exhibit colonic immune dysregulation and abnormal epithelium•Tnfr1−/− mice have reduced cytokine expression during a critical weaning period Although anti-TNF therapies are used to treat colitis, Liu et al. demonstrate that colitis-susceptible mice deficient for TNF receptor 1 (TNFR1) paradoxically develop severe disease shortly after weaning. TNFR1 function can be traced back to its mediation of pro-inflammatory responses during a critical period of immune development in early life.