A central controversy in the field of mucosal inflammation may be stated as follows (Figure 1 provides a pictorial representation of this): Is mucosal inflammation a reflection of a leukocyte-driven immune response that has gone awry, resulting in tissue injury and the loss of mucosal barrier function ( Figure 1A )? Or is it the mucosa itself, long known to play a role as a primary immune organ that is capable of producing a large number of pro-inflammatory molecules, that somehow has developed an exaggerated response that then leads to mu- Flagellin (58) 6 Diacyl Lipopeptides (144) Lipoteichoic acid (131) Zymosan (131) 7 Single-stranded RNA (145, 146) Imidazoquinoline (59) 8 Single-stranded RNA (146) Imidazoquinoline (147) 9 Bacterial (demethylated CpG) DNA (148) 10 Unknown 11 Profilin (149) Uropathogenic Bacteria (114) Figure 1 . Mechanisms by which TLR signaling leads to mucosal inflammation. As stated in the text, there are two potential mechanisms by which TLR signaling can lead to the development of mucosal inflammation. (A) TLR activation in response to DAMPs (damage associated molecular patterns) and PAMPs (pathogen associated molecular patterns) on leukocytes leads to the release of pro-inflammatory cytokines, resulting in epithelial destruction. (B) TLR activation by DAMPs and PAMPs on the epithelium itself directly impairs epithelial function and initiates the release of cytokines, leading to the development of mucosal inflammation. The development of mucosal inflammation likely arises from a combination of these mechanisms.