Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression.
Flagellin, the structural component of bacterial flagella, is secreted by pathogenic and commensal bacteria. Flagellin activates proinflammatory gene expression in intestinal epithelia. However, only flagellin that contacts basolateral epithelial surfaces is proinflammatory; apical flagellin has no effect. Pathogenic Salmonella, but not commensal Escherichia coli, translocate flagellin across epithelia, thus activating epithelial proinflammatory gene expression. Investigating how epithelia detect flagellin revealed that cell surface expression of Toll-like receptor 5 (TLR5) conferred NF-kappaB gene expression in response to flagellin. The response depended on both extracellular leucine-rich repeats and intracellular Toll/IL-1R homology region of TLR5 as well as the adaptor protein MyD88. Furthermore, immunolocalization and cell surface-selective biotinylation revealed that TLR5 is expressed exclusively on the basolateral surface of intestinal epithelia, thus providing a molecular basis for the polarity of this innate immune response. Thus, detection of flagellin by basolateral TLR5 mediates epithelial-driven inflammatory responses to Salmonella.
Gewirtz
A T
AT
Epithelial Pathobiology Division, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA ski@gene.com.
Navas
T A
TA
Lyons
S
S
Godowski
P J
PJ
Madara
J L
JL
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D003106:Colon; D029721:Drosophila Proteins; D005408:Flagellin / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D014162:Transfection
D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D005408:Flagellin