Danger-associated molecular patterns and inflammatory bowel disease: is there a connection?

The innate immune system is of critical importance for maintaining the local tissue homeostasis in the intestinal mucosa. It must recognize and rapidly respond to microbial antigens and danger signals to provide a first line of host defense. This is primarily accomplished through an array of pattern recognition receptors that are located in distinct (sub)cellular compartments and bind pathogen-associated and danger-associated molecular patterns (PAMPs and DAMPs, respectively). The impact of PAMPs, in particular NOD2/CARD15, in the pathogenesis of Crohn's disease is widely established. The involvement of DAMPs in the pathogenesis of inflammatory bowel disease (IBD), however, is much less recognized. DAMPs (also known as alarmins) represent non-pathogen-derived molecules, such as intracellular proteins released from damaged and stressed cells. Although the ligand(s) for the triggering receptor expressed on myeloid cells (TREM)-1 have not yet been fully identified, circumstantial evidence indicates that DAMPs are the inducers of the TREM-1-mediated, excessive induction of proinflammatory effects, also seen in patients with active IBD. Blocking the interactions between TREM-1 with its ligand(s) by the administration of a TREM-1-derived antagonistic peptide even attenuates the progression of established colonic inflammation. Hence, DAMPs can contribute to, and exacerbate, colonic inflammation in mouse models of IBD, in particular when they trigger innate immune cells of the intestinal lamina propria. DAMPs and PAMPs, however, may also be required for maintaining intestinal epithelial barrier functions as demonstrated by the enhanced susceptibility for colitis development in mice deficient for the NLRP6 or NLRC4 sensors in inflammasomes in intestinal epithelial cells.