Sensing of Commensal Organisms by the Intracellular Sensor NOD1 Mediates Experimental Pancreatitis

Abstract

SUMMARY The intracellular sensor NOD1 has important host defense functions relating to a variety of pathogens. Here we showed that this molecule also participated in the induction of a non-infectious pancreatitis via its response to commensal organisms. Pancreatitis induced by high-dose cerulein (a cholecystokinin receptor agonist) administration depends on NOD1 stimulation by gut microflora. To analyze this NOD1 activity we induced pancreatitis by simultaneous administration of low-dose of cerulein (that does not itself induce pancreatitis) and FK156, an activator of NOD1 that mimics the effect of gut bacteria that have breached the mucosal barrier. The pancreatitis was dependent on acinar cell production of the chemokine MCP-1 and the intra-pancreatic influx of CCR2+ inflammatory cells. Moreover, MCP-1 production involved activation of the transcription factors NF-κB and STAT3, each requiring complementary NOD1 and cerulein signaling. These studies indicate that gut commensals enable non-infectious pancreatic inflammation via NOD1 signaling in pancreatic acinar cells.

Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

“…More interestingly, this analysis also showed that poly (I:C) injection was accompanied by a marked increase in a group of five chemokines, CXCL9, CXCL10, CXCL11, CCL2, and CCL5 in both serum and pancreatic lysates that are tightly regulated by type I IFNs ( Fig. 1D) (25,32). These findings prompted us to measure IFN-a and IFN-b serum levels in mice treated with poly (I:C), and indeed, we found that poly (I:C) injection led to a marked elevation of IFN-a and IFN-b serum levels (Fig.…”

“…Pancreatic lysates were prepared as described previously (25). Pancreatic lysates (100 mg) and serum (100 ml) were applied to a commercial membrane with bound mouse cytokine array panel A (R&D Systems, Minneapolis, MN) to screen for cytokine and chemokine profiles.…”

MicroRNAs: Decoders of Dysbiosis into Metabolic Diseases?

“…Importantly, besides the well-established age-induced modification of gut microbiota [44], clear evidences between the link of pancreas health and sensing of microbial antigens have been provided by several publications. In fact, in this context, the NOD1-mediated experimental pancreatitis [45], the impact of TLR-4 on the severity of acute pancreatitis and pancreatitisassociated lung injury in mice [46] as well as the impact of TLR-7 on pancreatic carcinogenesis both in humans and mice [47] have been demonstrated. Thus, it appears clear that a dysbiosis-induced altered production of multiple microbial antigens such as peptides derived from bacterial cell wall and containing for instance D-glutamyl-mesodiaminopimelic acid (iE-DAP) moiety (recognized by NOD1), lipopolysaccharides (LPS, recognized by TLR-4) and single-stranded microbial RNA (recognized by TLR-7) may drive pancreatitis.…”

NOD-like receptors mediated activation of eosinophils interacting with bronchial epithelial cells: a link between innate immunity and allergic asthma

“…10 Among these PRRs, members of the intracellular NLR family including NOD1 and NOD2 have been identified as key mediators in inflammatory and immune responses, by recognizing intracellular microbes and commensal organisms. [11][12][13] NOD2 can also function as a cytoplasmic viral PRR by producing of interferonb.…”