Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis

Steven J McElroy; Lawrence S Prince; Jörn-Hendrik Weitkamp; Jeff Reese; James C Slaughter; D. Brent Polk

doi:10.1152/ajpgi.00550.2010

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Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis

Journal article

Open access

Peer reviewed

Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis

Steven J McElroy, Lawrence S Prince, Jörn-Hendrik Weitkamp, Jeff Reese, James C Slaughter and D. Brent Polk

American journal of physiology: Gastrointestinal and liver physiology, Vol.301(4), pp.G656-G666

10/2011

DOI: 10.1152/ajpgi.00550.2010

PMCID: PMC3191555

PMID: 21737776

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Abstract

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. NEC is believed to occur when intestinal bacteria invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Mucins are produced and secreted by epithelial goblet cells as a key component of the innate immune system and barrier function of the intestinal tract that help protect against bacterial invasion. To better understand the role of mucins in NEC, we quantified the number of mucus-containing small intestinal goblet cells present in infants with NEC and found they had significantly fewer goblet cells and Paneth cells compared with controls. To test whether inflammation has a developmentally dependent effect on intestinal goblet cells, TNF-α was injected into mice at various stages of intestinal development. TNF-α caused a loss of mucus-containing goblet cells only in immature mice and induced Muc2 and Muc3 mRNA upregulation only in mature ileum. Only minimal changes were seen in apoptosis and in expression of markers of goblet cell differentiation. TNF-α increased small intestinal mucus secretion and goblet cell hypersensitivity to prostaglandin E2 (PGE 2 ), a known mucus secretagogue produced by macrophages. These TNF-α-induced changes in mucus mRNA levels required TNF receptor 2 (TNFR2), whereas TNF-α-induced loss of mucus-positive goblet cells required TNFR1. Our findings of developmentally dependent TNF-α-induced alterations on intestinal mucus may help explain why NEC is predominantly found in premature infants, and TNF-α-induced alterations of the intestinal innate immune system and barrier functions may play a role in the pathogenesis of NEC itself.

Muc2

goblet cells

Mediators

Inflammation

mucus secretion

cytokines

intestinal inflammation

Immunity

Details

Title: Subtitle: Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis
Creators: Steven J McElroy - Departments of
Lawrence S Prince - Departments of
Jörn-Hendrik Weitkamp - Departments of
Jeff Reese - Departments of
James C Slaughter - Biostatistics, and
D. Brent Polk - Departments of
Resource Type: Journal article
Publication Details: American journal of physiology: Gastrointestinal and liver physiology, Vol.301(4), pp.G656-G666
DOI: 10.1152/ajpgi.00550.2010
PMID: 21737776
PMCID: PMC3191555
NLM abbreviation: Am J Physiol Gastrointest Liver Physiol
ISSN: 0193-1857
eISSN: 1522-1547
Publisher: American Physiological Society
Grant note: P30DK058404; K08DK083677; K08HD061607; HL097195; HL086324; HL77395; HL96967; R01DK56008; P30DK058404 / National Institutes of Health
Language: English
Date published: 10/2011
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics
Record Identifier: 9984093220402771

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