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.