Purpose of review Acute pancreatitis (AP) is associated with alcohol abuse gallstones and bacterial infection. to disease pathology in many models of experimental pancreatitis PF-04979064 has been PF-04979064 found to be a promising target for treatment of pancreatitis. Interestingly a direct activator of TLR4 the bacterial cell wall component in Gram negative bacteria lipopolysaccharide (LPS) contributes to the onset and severity of disease when combined with additional stressors such as chronic alcohol feeding however recent studies have shown that acute infection of mice with live bacteria is alone sufficient to induce acute pancreatitis. Summary In the last several months the convergent roles of acinar cell stress autophagy and proinflammatory signaling initiated by the toll-like receptors have been emphatically reinforced PF-04979064 in the onset of acute pancreatitis. infection induces activation of a process known as “xenophagy” where the autophagic response is brought to bear to destroy the pathogen [38]. p62 assembles on the microbes to direct them to the autophagosome. This response involves the phosphorylation of p62 and the induction of Nrf2 an indicator of oxidative stress. Thus bacterial invasion of the acinar cells is capable of evoking a cell autonomous response similar to what is found in PF-04979064 in more reductive models of pancreatitis. It will be interesting to examine if infection also induces an impaired autophagic flux in acinar cells together with stress and other pro-inflammatory pathways. Conclusions Acute pancreatitis is strongly associated with the activation of the pro-inflammatory NFκB pathway[21] often through activation of TLR4 on both inflammatory and acinar cells in collaboration with cellular stress and a defective autophagic flux in the acinar cells. Systemic TLR4 activation by LPS is sufficient to induce an inflammatory response that includes extensive infiltration into the pancreas but not sufficient to induce the acinar cell stress responses that are equally complicit in disease pathology[34]. On the other hand targeting TLR4 activity is emerging as a very effective method of ameliorating pancreas damage even after disease onset [28 33 suggesting that even though its activation is not sufficient to induce pancreatitis it is necessary. Coxsackievirus has long been known to be an infectious agent that by itself is capable of inducing pancreatitis in patients and animal models in part due to its direct infection of the pancreatic cells[39]. Consistent with other pancreatitis models coxsakievirus infection induces autophagy within the cells the virus infects [40]. Now we know that infection is capable of direct invasion of pancreas cells and capable of inducing a pancreatitis response. Future studies will determine of infection? Does antibiotic therapy fully resolve induced disease after it is initiated? Answering these Rabbit polyclonal to ACER3. questions will guide us down an intriguing path to understanding how inflammatory and autophagy signaling conspire to determine the fate of pancreatitis and how we may be able to effectively break up this conspiracy. ? Key Points Defective autophagic flux in acinar cells is associated with most pancreatitis models. TLR4/NFκB signaling in macrophages PF-04979064 is complicit in pancreatitis initiation. TLR4 signaling is a viable therapeutic target for pancreatitis treatment. While bacterial lipopolysaccharide can exacerbate but not initiate pancreatitis in mouse models infection alone is sufficient to induce the disease. Acknowledgements Supported by National Institutes of Health (NIH) grants R01CA 159222 and R01CA136754 to H.C.C Abbreviations TLRToll-like receptorLPSlipopolysaccharideIKKInhibitor of kappa B KinaseNFκBNuclear Factor kappa BTCPTPT-cell Protein Tyrosine PhosphataseCORM2Carbon Monoxide Releasing Molecule 2EREndoplasmic Reticulum Footnotes Conflicts None References and recommended reading Papers of particular interest published within the annual period of review (18 months/ 2012-2013) have been highlighted as: ? of special interest ?? of outstanding interest 1 Peery AF Dellon ES Lund J Crockett SD McGowan CE Bulsiewicz WJ Gangarosa LM Thiny MT Stizenberg K Morgan DR Ringel Y et al. Burden of gastrointestinal disease in the united states: 2012 update. Gastroenterology. 2012;143(5):1179-1187. e1171-e1173. [PMC free article] PF-04979064 [PubMed] 2 Yadav D Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1252-1261. [PMC free article] [PubMed] 3 Testoni PA Caporuscio S Bagnolo.