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

doi:10.1016/j.celrep.2020.108275

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^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

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.

Original language	English (US)
Article number	108275
Journal	Cell reports
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2020.108275
State	Published - Oct 20 2020

Funding

This study was supported by the U.S. National Institutes of Health ( R01-DK056008 and R01-DK108648 , to D.B.P.), the Crohn's and Colitis Foundation (career development award to C.Y.L., postdoctoral fellowship to P.E.D., and senior research award to D.B.P.), and the California Institute for Regenerative Medicine (postdoctoral fellowship to C.Y.L.). We would like to thank Tsen-Yin Lin, Michael Sheard, Elizabeth Lopez, Gricelda Vasquez, and Chris Escolano for technical advice and care of animals.

Keywords

IBD
antibiotics
barrier
microbiome
mucosa
tolerance
weaning reaction

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2020.108275

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title = "TNF Receptor 1 Promotes Early-Life Immunity and Protects against Colitis in Mice",

abstract = "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.",

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author = "Liu, {Cambrian Y.} and Tam, {Sharon S.} and Ying Huang and Dub{\'e}, {Philip E.} and Rabea Alhosh and Nandini Girish and Shivesh Punit and Shirin Nataneli and Fan Li and Bender, {Jeffrey M.} and Washington, {M. Kay} and Polk, {D. Brent}",

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AU - Liu, Cambrian Y.

AU - Tam, Sharon S.

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AU - Dubé, Philip E.

AU - Alhosh, Rabea

AU - Girish, Nandini

AU - Punit, Shivesh

AU - Nataneli, Shirin

AU - Li, Fan

AU - Bender, Jeffrey M.

AU - Washington, M. Kay

AU - Polk, D. Brent

PY - 2020/10/20

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N2 - 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.

AB - 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.

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KW - barrier

KW - microbiome

KW - mucosa

KW - tolerance

KW - weaning reaction

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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