Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells

Abstract

Enteropathogenic bacteria elicit mucosal innate and adaptive immune responses. We investigated whether gut epithelial cells played a role in triggering an adaptive immune response by recruiting dendritic cells (DCs). Immature DCs are selectively attracted by the CCL20 chemokine. The expression of the CCL20 gene in human intestinal epithelial cell lines was up-regulated by pathogenic bacteria, including Salmonella species, but not by indigenous bacteria of the intestinal flora. The Salmonella machinery for epithelial cell invasion was not required for CCL20 gene activation. Flagellin but not the lipopolysaccharide was found to be the Salmonella factor responsible for stimulation of epithelial CCL20 production. CCL20 in turn triggered a specific migration of immature DCs. Our data show that crosstalk between bacterial flagellin and epithelial cells is essential for the recruitment of DCs, a mechanism that could be instrumental to initiate adaptive immune responses in the gut.

TLR Signaling in the Gut in Health and Disease

“…Given that luminal, non-pathogenic bacteria are located apically and should not secrete monomeric flagellin (12), any basolateral bacteria must have breached the epithelial barrier and should be considered a de facto pathogen. Flagellin derived from Salmonella species but not commensal bacteria is able to stimulate secretion of the chemokine CCL20 by IEC, which in turn recruits immature dendritic cells to the intestinal epithelium (13). TLR5 activation also stimulates secretion of the chemokines IL-8 and MIP3␣ (14).…”

Pseudomonas aeruginosa Flagellin and Alginate Elicit Very Distinct Gene Expression Patterns in Airway Epithelial Cells: Implications for Cystic Fibrosis Disease

“…Other cell types, including monocytes, respond to flagellin inducing the production of proinflammatory cytokines (31). Furthermore, flagellin plays a role in triggering adaptive immune responses by stimulating chemokine secretion and migration and maturation of dendritic cells (32,33), and by modulating T cell activation in vivo (34). Flagellin is the ligand of TLR-5 (35,36), although additional receptors may modulate signaling (37,38).…”

Mucosal interplay among commensal and pathogenic bacteria: Lessons from flagellin and Toll‐like receptor 5

“…1C) [8,37]. Flagellin triggers the transient epithelial expression of the DC-specific chemokine CCL20 (also known as MIP-3-alpha or LARC) that in turn attracts immature DCs [42]. Interestingly, HAL author manuscript inserm-00071278, version 1 ccl20 expression in Peyer's patch epithelium is associated to sub-epithelial positioning of DCs producing CCR6, the CCL20-specific receptor and to induction of mucosal adaptive immune responses [43,44].…”