Recent studies have linked the ER stress sensor IRE1α with the RIG-I pathway, which triggers an inflammatory response upon detection of viral RNAs. In response to ER dysfunction, IRE1α cleaves mRNA into single-strand fragments that lack markers of self, which activate RIG-I. Certain microbial products from mucosal pathogens activate this pathway by binding IRE1α directly, and the discovery that IRE1 is amplified at mucosal surfaces by gene duplication suggests an important role for IRE1 in mucosal immunity. Here, we review evidence in support of this hypothesis, and propose a model wherein IRE1 surveys the integrity of the ER, acting as a guard receptor and a pattern recognition receptor, capable both of sensing cellular stress caused by microbial infection and of responding to pathogens directly.

BACKGROUND: Intestinal peristalsis is a dynamic physiologic process influenced by dietary, microbial and inflammatory changes at the mucosal site. It is tightly regulated by enteric nervous system through complex interactions with other cell types. IBD related disturbances of normal ENS function results in altered peristaltic activity or gastrointestinal (GI) dysmotility. GI dysmotility often remains a problem even during remission phase when the mucosal inflammation is controlled. It is thought that inflammatory environment promotes expansion and differentiation of stem cell into new neurons. However, the exact cellular mechanisms that drive IBD related enteric neuropathy are poorly understood. METHODS: Homeostasis of intestinal macrophages in vivo, selective depletion of muscularis macrophages in vivo, functional studies of gastrointestinal motility in vivo and ex vivo, enteric neuron phenotype and function in vitro and in vivo. RESULTS: A distinct population of macrophages is distributed in the intestinal muscularis externa. Here we identify a novel mechanism by which muscularis macrophages regulate ENS function during the steady state. Specifically, we demonstrate that in the steady state muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which alters the activity of enteric neurons expressing BMP receptor. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, commensal stimuli regulate BMP2 expression by macrophages. CONCLUSIONS: Our findings define a central role of innate immune cells in regulating gastrointestinal physiology and uncover a mutualistic relationship between the enteric nervous and immune systems. We propose that macrophageneuronal crosstalk is dynamic and can be influenced by the changes at the mucosal site. Muscularis macrophages are likely the cell type that drives the development of enteric neuropathy during IBD. P-225TLR9 Mediates Host Inflammatory Response in Clostridium difficile Infection BACKGROUND: Clostridium difficile infection (CDI) is the leading recognized cause of nosocomial infectious diarrhea in the developed world. The importance of CDI amongst patients with inflammatory bowel disease (IBD) is increasingly being recognized. Recent studies on CDI in IBD patients have demonstrated a concerning trend towards increased rates of infection, morbidity, mortality and healthcare costs. Guidelines now promote testing for C. difficile in IBD patients experiencing a relapse of colitis. The major virulent factors of C. difficile are 2 large protein exotoxins-A and B, which initiate a marked intestinal inflammatory response. We serendipitously discovered that toxins secreted by Clostridium difficile contain significant amounts of DNA, which was further confirmed (by sequencing) to be of C. difficile origin. It is known that toll-like receptor 9 (TLR9) recognizes bacterial DNA and triggers an i...