Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells

Abstract

Salmonella sneaks past security C ertain gut cells can leave resident bacteria alone but respond selectively to invaders. Satoshi Uematsu, Shizuo Akira, and colleagues (Osaka University, Japan) suggest that gut cells achieve this differentiation by using a special, pathogen-specifi c receptor called the Toll-like receptor 5 (TLR5). But the pathogenic Salmonella typhimurium turns the situation around: events triggered by the special receptor help the bug to invade its host. TLRs, which are expressed on professional antigen-presenting cells, recognize common pathogen-associated molecules and trigger innate immunity. TLR5 on dendritic cells recognizes bacterial fl agellin protein in vitro, but its function in vivo was previously unknown. Akira's team found that TLR5 mRNA was highly expressed in the mouse intestine particularly in a specifi c subpopulation of antigen-presenting lamina propria cells (CD11c + LPCs). In these cells, TLR5 was necessary for bacterial fl agellin to induce infl ammatory cytokines, yet when the team infected TLR5 −/− mice with Salmonella, a fl agellated bacterium, these mice were unexpectedly resistant to the bug. It was not, however, invasion of the CD11c + LPCs that showed a difference. In the gut, Salmonella invaded the CD11c + LPCs in both TLR5 +/+ and TLR5 −/− mice. However, in the TLR5 −/− mice, fewer bacteria-laden CD11c + LPCs moved from the intestinal tract to the mesenteric lymph nodes, probably because the LPCs failed to be activated by the bacteria. These mice had more resistance to systemic infection-fewer bacteria reached their livers and spleens-but it is not yet clear whether a similar tactic of TLR5 blocking would work in humans.

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

“…A common stop codon polymorphism in TLR5 is associated to both increased susceptibility to pneumonia caused by the flagellated bacteria Legionella pneumophila and resistance to Crohn's disease, indicating that TLR5 signalling is relevant for mucosal immunity [20,21]. With TLR5-deficient mice, the critical role of TLR5 in mucosal inflammatory responses was established because deletion of Tlr5 gene alters response to respiratory, intestinal and urinary tract infections as well as mucosal homeostasis [1,[22][23][24][25][26]. Parenchyma and haematopoietic cells play a different role in TLR5-dependent mucosal immunity depending on the tissue studied.…”

“…In the gut, dendritic cells of the lamina propria, i.e. haematopoietic cells, have been shown to be instrumental in TLR5 signalling [23]. Using chimeric mice with WT or Tlr5 À/À BM, Feuillet et al observed that TNF-a and IL-6 production in BALF after flagellin administration is dependent on haematopoietic and radioresistant cells whereas lung neutrophil infiltration mainly required TLR5-competent non-haematopoietic cells [22].…”

“…Furthermore, respiratory pathogens that reach the basolateral side of the epithelial barrier via specific transport mechanisms or following trauma can stimulate either epithelial cells, airway smooth muscle, endothelial cells or any TLR5-expressing haematopoietic cells (such as lung macrophages and dendritic cells). Notably, the intestine's innate response to flagellin relies on dendritic cell activation [1,23,39]. This compartmentalization may control the production of proinflammatory responses to signals from the gut's microbial flora.…”

Lamina propria dendritic cells: For whom the bell TOLLs?

“…This report [9] suggests a fascinating hypothesis of separation of labour, as well as a mutual control, between different antigen presenting cell populations. To further complicate the picture of LP DC functions, it has been shown that LP DC do not express Toll-like receptor (TLR) 4 and are refractory to lipopolysaccharide (LPS), while they express TLR5 and respond to flagellin by releasing inflammatory cytokines [12].…”

“…This would result in the downregulation of TLR and the inability to release IL-12. It would also be interesting to know whether these CD11c hi cells express TLR5 and are still responsive to flagellin [12].…”