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

Cambrian Y. Liu; Sharon S. Tam; Ying Huang; Philip E. Dubé; Rabea Alhosh; Nandini Girish; Shivesh Punit; Shirin Nataneli; Fan Li; Jeffrey M. Bender; M. Kay Washington; D. Brent Polk

Cell Reports (Oct 2020)

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

Cambrian Y. Liu,
Sharon S. Tam,
Ying Huang,
Philip E. Dubé,
Rabea Alhosh,
Nandini Girish,
Shivesh Punit,
Shirin Nataneli,
Fan Li,
Jeffrey M. Bender,
M. Kay Washington,
D. Brent Polk

Affiliations

Cambrian Y. Liu: Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Sharon S. Tam: Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Ying Huang: Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Philip E. Dubé: Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Rabea Alhosh: Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Nandini Girish: Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Shivesh Punit: Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Shirin Nataneli: Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Fan Li: Division of Infectious Diseases, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Jeffrey M. Bender: Division of Infectious Diseases, Children’s Hospital Los Angeles, Los Angeles, CA, USA
M. Kay Washington: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
D. Brent Polk: Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA; Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; Corresponding author

Journal volume & issue: Vol. 33, no. 3
p. 108275

Abstract

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Summary: 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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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