A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis

Ryan Ungaro, Masayuki Fukata, David Hsu, Yasmin Hernandez, Keith Breglio, Anli Chen, Ruliang Xu, John Sotolongo, Cecillia Espana, Julia Zaias, Greg Elson, Lloyd Mayer, Marie Kosco-Vilbois, Maria T Abreu

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

Dysregulated innate immune responses to commensal bacteria contribute to the development of inflammatory bowel disease (IBD). TLR4 is overexpressed in the intestinal mucosa of IBD patients and may contribute to uncontrolled inflammation. However, TLR4 is also an important mediator of intestinal repair. The aim of this study is to examine the effect of a TLR4 antagonist on inflammation and intestinal repair in two murine models of IBD. Colitis was induced in C57BL/6J mice with dextran sodium sulfate (DSS) or by transferring CD45Rbhi T cells into RAG1-/- mice. An antibody (Ab) against the TLR4/MD-2 complex or isotype control Ab was administered intraperitoneally during DSS treatment, recovery from DSS colitis, or induction of colitis in RAG1-/- mice. Colitis severity was assessed by disease activity index (DAI) and histology. The effect of the Ab on the inflammatory infiltrate was determined by cell isolation and immunohistochemistry. Mucosal expression of inflammatory mediators was analyzed by real-time PCR and ELISA. Blocking TLR4 at the beginning of DSS administration delayed the development of colitis with significantly lower DAI scores. Anti-TLR4 Ab treatment decreased macrophage and dendritic cell infiltrate and reduced mucosal expression of CCL2, CCL20, TNF-α, and IL-6. Anti-TLR4 Ab treatment during recovery from DSS colitis resulted in defective mucosal healing with lower expression of COX-2, PGE 2, and amphiregulin. In contrast, TLR4 blockade had minimal efficacy in ameliorating inflammation in the adoptive transfer model of chronic colitis. Our findings suggest that anti-TLR4 therapy may decrease inflammation in IBD but may also interfere with colonic mucosal healing.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number6
DOIs
StatePublished - Jun 1 2009

Fingerprint

Toll-Like Receptor 4
Colitis
Dextran Sulfate
Inflammation
Antibodies
Inflammatory Bowel Diseases
Anti-Idiotypic Antibodies
Adoptive Transfer
Cell Separation
Therapeutics
Intestinal Mucosa
Prostaglandins E
Inbred C57BL Mouse
Innate Immunity
Dendritic Cells
Real-Time Polymerase Chain Reaction
Interleukin-6
Histology
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry

Keywords

  • Antigen presenting cells
  • Inflammatory bowel disease
  • Innate immunity

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. / Ungaro, Ryan; Fukata, Masayuki; Hsu, David; Hernandez, Yasmin; Breglio, Keith; Chen, Anli; Xu, Ruliang; Sotolongo, John; Espana, Cecillia; Zaias, Julia; Elson, Greg; Mayer, Lloyd; Kosco-Vilbois, Marie; Abreu, Maria T.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 296, No. 6, 01.06.2009.

Research output: Contribution to journalArticle

Ungaro, Ryan ; Fukata, Masayuki ; Hsu, David ; Hernandez, Yasmin ; Breglio, Keith ; Chen, Anli ; Xu, Ruliang ; Sotolongo, John ; Espana, Cecillia ; Zaias, Julia ; Elson, Greg ; Mayer, Lloyd ; Kosco-Vilbois, Marie ; Abreu, Maria T. / A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2009 ; Vol. 296, No. 6.
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AU - Sotolongo, John

AU - Espana, Cecillia

AU - Zaias, Julia

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AU - Kosco-Vilbois, Marie

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AB - Dysregulated innate immune responses to commensal bacteria contribute to the development of inflammatory bowel disease (IBD). TLR4 is overexpressed in the intestinal mucosa of IBD patients and may contribute to uncontrolled inflammation. However, TLR4 is also an important mediator of intestinal repair. The aim of this study is to examine the effect of a TLR4 antagonist on inflammation and intestinal repair in two murine models of IBD. Colitis was induced in C57BL/6J mice with dextran sodium sulfate (DSS) or by transferring CD45Rbhi T cells into RAG1-/- mice. An antibody (Ab) against the TLR4/MD-2 complex or isotype control Ab was administered intraperitoneally during DSS treatment, recovery from DSS colitis, or induction of colitis in RAG1-/- mice. Colitis severity was assessed by disease activity index (DAI) and histology. The effect of the Ab on the inflammatory infiltrate was determined by cell isolation and immunohistochemistry. Mucosal expression of inflammatory mediators was analyzed by real-time PCR and ELISA. Blocking TLR4 at the beginning of DSS administration delayed the development of colitis with significantly lower DAI scores. Anti-TLR4 Ab treatment decreased macrophage and dendritic cell infiltrate and reduced mucosal expression of CCL2, CCL20, TNF-α, and IL-6. Anti-TLR4 Ab treatment during recovery from DSS colitis resulted in defective mucosal healing with lower expression of COX-2, PGE 2, and amphiregulin. In contrast, TLR4 blockade had minimal efficacy in ameliorating inflammation in the adoptive transfer model of chronic colitis. Our findings suggest that anti-TLR4 therapy may decrease inflammation in IBD but may also interfere with colonic mucosal healing.

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