Inhibition of RIPK1-dependent regulated acinar cell necrosis provides protection against acute pancreatitis via the RIPK1/NF-κB/AQP8 pathway

Abstract

Currently, preliminary results have confirmed the existence of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis of pancreatic acinar cells during early acute pancreatitis (AP), which might be a potential target for the effective regulation of necroinflammatory injury. However, the exact effect of receptor-interacting protein kinase 1 (RIPK1)-dependent regulated acinar cell necrosis on AP is still uncertain. In our study, we first explored the changes in the degree of local and systemic inflammation in AP rats when the activation of acinar cell RIPK1 was inhibited. The RIPK1 inhibitor Nec-1 was used to treat rats, and the levels of related inflammatory markers, necrosis indicators and apoptotic indicators were measured. Changes in pancreatic nuclear factor κB (NF-κB) and aquaporin 8 (AQP8) expression were noted. Next, the expression of AQP8 in AR42J cells was inhibited, and the degree of cell necrosis and inflammatory damage was found to be significantly reduced. Most importantly, we demonstrated that the RIPK1/NF-ĸB/AQP8 axis might be a potential regulatory pathway mediating RIPK1-dependent regulated acinar cell necrosis in early AP. Finally, we used the NF-κB inhibitor PDTC and Nec-1 to treat rats in different groups and measured the degree of pathological pancreatic injury, the activation of RIPK1, and the expression of NF-κB and AQP8. In summary, we hypothesized that there might be a RIPK1/NF-ĸB/AQP8 pathway controlling RIPK1-dependent regulated necrosis of acinar cells in AP, which might be a promising therapeutic target against AP-related injury.

Necrostatin-1 and necroptosis inhibition: Pathophysiology and therapeutic implications

“…In fact, Nec-1 is indeed associated with systemic inflammation. In the rat model of acute pancreatitis, rats treated with Nec-1 displayed significant milder symptoms and pathophysiological characteristics, and Nec-1 alleviated the extent of systemic inflammatory response caused by acute pancreatitis, the underlying mechanism of this protective effect is probably related to RIP1/NF-κB p65/AQP8 axis [ 195 ]. Although there is no research directly showing the relation between necroptosis and COVID-19, or the effect of Nec-1 in COVID-19, the strong anti-inflammation ability of Nec-1 makes us predict that Nec-1/Nec-1 analogues might have the capability to alleviate cytokine storm, systemic inflammation and thus COVID-19.…”

Necroptosis protects against exacerbation of acute pancreatitis

“…Regarding the contribution of necroptosis to the pathophysiology of AP, it is unclear whether inhibition of necroptosis mediated by RIPK3/MLKL is effective in protecting against pancreatic damage because different outcomes have been reported. Inhibition of necroptosis with the RIPK1 inhibitor necrostatin-1 or by genetic deletion of either Ripk3 or Mlkl provides protection against AP by reducing acinar cell vacuolization and necrosis 15 – 19 . In contrast, necrotizing pancreatitis is accelerated in Ripk3 -deficient mice 20 .…”

Role of ROCK/NF‑κB/AQP8 signaling in ethanol‑induced intestinal epithelial barrier dysfunction

“…However, NF-κB inhibition in IBS model rats did not fully restore the intestinal epithelium ( 13 ). Furthermore, Duan et al ( 31 ) found that the early acute receptor-interacting protein kinase 1 (RIPK1)/NF-κB/AQP8 axis mediated the RIPK1-dependent acinar cell necrosis. Consistent with this, the present study suggested that the NF-κB-mediated regulation of AQP8 expression was likely to be involved in ethanol-induced IEB dysfunction.…”