Cited by 159Inflammatory Bowel DiseaseImmune Response and InflammationOcular Diseases and Behçet’s Syndrome

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

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Ungaro, Ryan, Fukata, Masayuki, Hsu, David, Hernandez, Yasmin, Breglio, Keith, Chen, Anli, Xu, Ruliang, Sotolongo, John +6 more·2009·American Journal of Physiology-Gastrointestinal and Liver Physiology

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 CD45Rb(hi) 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-alpha, 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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Crossref · 10.1152/ajpgi.90496.2008

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  • Blocking TLR4 with antibodies limited acute inflammation in the DSS model but hampered subsequent tissue repair, suggesting an important role for TLR4 in the resolution of inflammation and restoration of tissue integrity.

    “Although blocking TLR4 with antibodies limited acute inflammation in the DSS model, subsequent tissue repair was hampered, suggesting an important role for TLR4 in the resolution of inflammation and restoration of tissue integrity.162”

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Authors
Ungaro, R., Fukata, M., Hsu, D., Hernandez, Y., Breglio, K., Chen, A., Xu, R., Sotolongo, J., Espana, C., Zaias, J., Elson, G., Mayer, L., Kosco-Vilbois, M., & Abreu, M. T.
Affiliations
  • Mount Sinai Hospital (US)
  • University of Miami (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Light Chain Bioscience (Switzerland) (CH)
Venue
American Journal of Physiology-Gastrointestinal and Liver Physiology
Published
2009-06
Volume
296
Issue
6
Pages
G1167-G1179
ISSN
  • 0193-1857 (ISSN-L)
  • 1522-1547
OpenAlex
W2121908572
Cited by
159
References
81
Citations by year
2026: 4 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 10 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 6 · 2016: 7 · 2015: 11 · 2014: 12 · 2013: 18 · 2012: 19
FWCI
10.47
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute of Allergy and Infectious Diseases (AI-052266)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R21DK069594, DK069594)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
Keywords
TLR4, anti-TLR4 antibody, inflammatory bowel disease, colitis, mucosal healing, intestinal inflammation, MD-2, DSS-induced colitis, adoptive T cell therapy, macrophages, dendritic cells, MCP-1, CCL20, TNF-α, interleukin-6, cyclooxygenase-2, prostaglandin E2, amphiregulin
MeSH terms
Animals, Antibodies, Monoclonal, Antigen-Presenting Cells, Cell Movement, Colitis, Epithelial Cells, Female, Glycoproteins, Inflammation, Intestinal Mucosa, Lymph Nodes, Male, Mice, Inbred C57BL, Regeneration, T-Lymphocytes, Dinoprostone, Cytokines, Dextran Sulfate, Mice, Knockout, Homeodomain Proteins, Chemokines, Bacterial Translocation, Intercellular Signaling Peptides and Proteins, Cell Proliferation, Toll-Like Receptor 4, Mice, Cyclooxygenase 2, EGF Family of Proteins, Amphiregulin

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