Extracellular high mobility group box-1 (HMGB1) inhibits enterocyte migration via activation of toll-like receptor-4 and increased cell-matrix adhesiveness

Shipan Dai, Chhinder Sodhi, Selma Cetin, Ward Richardson, Maria Branca, Matthew D. Neal, Thomas Prindle, Congrong Ma, Richard A. Shapiro, Bin Li, James H C Wang, David Hackam

Research output: Contribution to journalArticle

Abstract

Toll-like receptor-4 (TLR4) is the receptor for bacterial lipopolysaccharide, yet it may also respond to a variety of endogenous molecules. Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in newborn infants and is characterized by intestinal mucosal destruction and impaired enterocyte migration due to increased TLR4 signaling on enterocytes. The endogenous ligands for TLR4 that lead to impaired enterocyte migration remain unknown. High mobility group box-1 (HMGB1) is a DNA-binding protein that is released from injured cells during inflammation. We thus hypothesize that extracellular HMGB1 inhibits enterocyte migration via activation of TLR4 and sought to define the pathways involved. We now demonstrate that murine and human NEC are associated with increased intestinal HMGB1 expression, that serum HMGB1 is increased in murine NEC, and that HMGB1 inhibits enterocyte migration in vitro and in vivo in a TLR4-dependent manner. This finding was unique to enterocytes as HMGB1 enhanced migration of inflammatory cells in vitro and in vivo. In seeking to understand the mechanisms involved, TLR4-dependent HMGB1 signaling increased RhoA activation in enterocytes, increased phosphorylation of focal adhesion kinase, and increased phosphorylation of cofilin, resulting in increased stress fibers and focal adhesions. Using single cell force traction microscopy, the net effect of HMGB1 signaling was a TLR4-dependent increase in cell force adhesion, accounting for the impaired enterocyte migration. These findings demonstrate a novel pathway by which TLR4 activation by HMGB1 delays mucosal repair and suggest a novel potential therapeutic target in the amelioration of intestinal inflammatory diseases like NEC.

Original languageEnglish (US)
Pages (from-to)4995-5002
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number7
DOIs
StatePublished - Feb 12 2010
Externally publishedYes

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Adhesiveness
Toll-Like Receptor 4
Enterocytes
Chemical activation
Necrotizing Enterocolitis
Phosphorylation
Adhesion
Actin Depolymerizing Factors
CD14 Antigens
Intestinal Diseases
Focal Adhesion Protein-Tyrosine Kinases
Stress Fibers
Focal Adhesions
Atomic Force Microscopy
Gastrointestinal Diseases
DNA-Binding Proteins
Traction
Cell Adhesion
Cell Movement
Lipopolysaccharides

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Extracellular high mobility group box-1 (HMGB1) inhibits enterocyte migration via activation of toll-like receptor-4 and increased cell-matrix adhesiveness. / Dai, Shipan; Sodhi, Chhinder; Cetin, Selma; Richardson, Ward; Branca, Maria; Neal, Matthew D.; Prindle, Thomas; Ma, Congrong; Shapiro, Richard A.; Li, Bin; Wang, James H C; Hackam, David.

In: Journal of Biological Chemistry, Vol. 285, No. 7, 12.02.2010, p. 4995-5002.

Research output: Contribution to journalArticle

Dai, Shipan ; Sodhi, Chhinder ; Cetin, Selma ; Richardson, Ward ; Branca, Maria ; Neal, Matthew D. ; Prindle, Thomas ; Ma, Congrong ; Shapiro, Richard A. ; Li, Bin ; Wang, James H C ; Hackam, David. / Extracellular high mobility group box-1 (HMGB1) inhibits enterocyte migration via activation of toll-like receptor-4 and increased cell-matrix adhesiveness. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 7. pp. 4995-5002.
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AU - Sodhi, Chhinder

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AU - Richardson, Ward

AU - Branca, Maria

AU - Neal, Matthew D.

AU - Prindle, Thomas

AU - Ma, Congrong

AU - Shapiro, Richard A.

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