CIP2A inhibitors TD52 and Ethoxysanguinarine promote macrophage autophagy and alleviates acute pancreatitis by modulating the AKT-mTOR pathway.

Background: Acute pancreatitis (AP) is a prevalent and serious condition within the digestive system, with approximately 20 % to 30 % of cases advancing to severe acute pancreatitis (SAP). During the initial phases of SAP, macrophages are activated in response to the substantial amounts of acinar cell contents and damage-associated molecular patterns (DAMPs) resulting from acinar cell destruction. Subsequently, activated macrophages release a significant array of pro-inflammatory factors that exacerbate the progression of SAP. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic protein that is intimately linked to immune regulation. While the role of CIP2A in T-cell-mediated specific immune responses has been reported, its function and mechanism in macrophages, a component of non-specific immunity, have not been widely studied. This research fills this knowledge gap by elucidating the critical role of CIP2A in regulating macrophage autophagy and inflammation. This finding not only expands our understanding of CIP2A in immune modulation but also provides a new scientific basis and potential application prospects for targeting CIP2A in the treatment of AP.

Methods: We established AP using a combination of palmitoleic acid with anhydrous ethanol or using caerulein alone. The effects of TD52 and Ethoxysanguinarine (Etho) on SAP were evaluated through serological, histopathological, and tissue inflammation observations. The effect of TD52 on macrophage activation in vitro was examined using primary macrophages (PMs) and RAW264.7 cells.

Results: We found that TD52 and Etho inhibit CIP2A expression while reducing the levels of serum amylase, lipase, and inflammatory cytokines, thereby alleviating the pathological symptoms of SAP. Additionally, TD52 could reduce the infiltration of macrophages into pancreatic tissue. Therefore, we established a model of macrophage inflammatory response mimicking the pathophysiological process of AP and detected changes in inflammation, apoptosis, and autophagy through pre-treatment of macrophages with TD52. The results show that inhibiting CIP2A expression decreases the release of inflammatory cytokines and reduces apoptosis in macrophages. Further exploration revealed that TD52 promoted macrophage autophagy regulation and inhibited the AKT-mTOR pathway to modulate macrophage activation.

Conclusion: In summary, our findings indicate that TD52 and Etho can alleviate the severity of SAP. TD52 can block the AKT-mTOR pathway to promote macrophage autophagy, thereby improving SAP. Thus, CIP2A may serve as one of the molecular targets in SAP, highlighting its potential as a therapeutic option.