Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli

Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4203-8. doi: 10.1073/pnas.0736473100. Epub 2003 Mar 24.


Innate host defenses at mucosal surfaces are critical in the early stages of many bacterial infections. In addition to cells of the traditional innate immune system, epithelial cells can also produce inflammatory mediators during an infection. However, the role of the epithelium in innate host defense in vivo is unclear. Recent studies have shown that lipopolysaccharide (LPS) recognition is critical for bladder epithelial cells to recognize and respond to Escherichia coli. Moreover, the LPS-nonresponsive mouse strain C3HHeJ, which has a mutation in the primary LPS receptor, Toll-like receptor 4 (TLR4), is extremely susceptible to infection with uropathogenic strains of E. coli. In this study, a bone marrow transplant approach was used to investigate the specific contributions of the bladder epithelium (and other stromal cells) in the TLR4-mediated innate immune response to the invading E. coli pathogen. Mice expressing the mutant TLR4 in the epithelialstromal compartment were not able to mount a protective inflammatory response to control the early infection even when their hematopoietic cells expressed wild-type TLR4. However, the presence of TLR4(+) epithelialstromal cells was not sufficient to activate an acute inflammatory response unless the hematopoietic cells were also TLR4(+). These results demonstrated that bladder epithelial cells play a critical role in TLR4-mediated innate immunity in vivo during a mucosal bacterial infection.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Transplantation / immunology
  • Bone Marrow Transplantation / physiology
  • Drosophila Proteins*
  • Escherichia coli / pathogenicity*
  • Female
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • Immunity, Innate
  • Inflammation / microbiology*
  • Inflammation / prevention & control
  • Lipopolysaccharides / pharmacology*
  • Major Histocompatibility Complex
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred Strains
  • Receptors, Cell Surface / physiology*
  • Stromal Cells / physiology*
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Transplantation Chimera
  • Urinary Bladder / cytology
  • Urinary Bladder / drug effects
  • Urinary Bladder / microbiology
  • Urinary Bladder / physiology*
  • Urothelium / drug effects
  • Urothelium / microbiology
  • Urothelium / physiology


  • Drosophila Proteins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors