rget for disease modifying therapies in TDP-43 proteinopathies. Clostridium difficile, a Gram-positive sporeforming anaerobic bacterium, is a leading cause of nosocomial diarrhea worldwide. Hospital outbreaks, the increased occurrence of community-acquired infections and the growing threat of antibiotic resistance highlight the need for new therapeutics to treat C. difficile infections . Through the release of two large toxins, toxin A and toxin B, C. difficile triggers intestinal tissue damage and a robust 487-52-5 site inflammatory response resulting in relapsing diarrhea, pseudomembranous colitis, toxic megacolon and, in severe cases, death. TcdA and TcdB are glucosyltransferases that glucosylate and inhibit monomeric G-proteins, such as Cdc42, Rho and Rac1, leading to changes in cytoskeletal function, cell rounding and the loss of intestinal epithelial barrier function. In addition to damaging the intestinal epithelial layer, TcdA and TcdB trigger the release of inflammatory mediators from intestinal epithelial cells and monocytes/macrophages. Toxin-induced CXCL8/IL-8 release from IECs is well documented and thought to play a key role in the recruitment of inflammatory cells into intestinal tissue. 1 P2Y6 Mediates IL-8 Release and Barrier Dysfunction One of the hallmarks of CDI is the massive influx of neutrophils into the colonic mucosa. This inflammatory response may play a role in controlling the severity of CDI, but may also contribute to its pathogenesis. Animal studies have indicated that the neutrophilic response is required to resolve CDI in the absence of a therapeutic intervention. Notably, Hasegawa et al. reported that Nod1-/- mice displayed more severe CDI, an observation linked to inadequate neutrophil recruitment and increased systemic bacterial translocation. On the other hand, the influx of neutrophils may contribute to the tissue damage observed in CDI. Studies targeting the early inflammatory responses triggered by TcdA and TcdB have reported reduced disease severity. Indeed strategies to neutralize TcdA and TcdB also proven effective in reducing CDI severity. We have previously reported that inhibiting the toxin-induced production of IL-1, and the subsequent immune cell infiltration, protected mice from toxin-induced intestinal tissue damage. Clinical studies have observed a strong correlation between elevated cytokine production and the severity CDI, a correlation that holds true even after the toxin burden was taken into account. These data suggest that an exaggerated immune response may contribute to the pathogenesis of CDI. In IECs, C. difficile toxins trigger cell stress and induce cell death through apoptosis and necrosis. In many cases, stressed or dying cells release a variety of endogenous mediators, such as ATP, UDP and HMGB1, that can activate receptors on neighboring cells. These substances, termed “danger signals”, are thought to initiate cellular 14579267 events that help the rid 
the system of the offending agent or enhance the removal of dead 11336787 cell material. Extracellular nucleotides, such as UDP, have been characterized as danger signals in a number of different systems and trigger the production of inflammatory mediators, such as CXCL8/IL-8 and increase the ability of macrophages to bind and phagocytose apoptotic bodies. In the context of the gastrointestinal tract, inflammatory stress has been reported to trigger the release of nucleotides, such as UDP, that can initiate tissue inflammation and following the production
