Irisin improves BBB dysfunction in SAP rats by inhibiting MMP-9 via the ERK/NF-κB signaling pathway.

Background: Blood-brain barrier (BBB) damage may lead to life-threatening pancreatic encephalopathy in patients with serious acute pancreatitis (SAP). Irisin alleviates BBB injury caused by cerebral ischemia-reperfusion by repressing matrix metalloproteinase-9 (MMP-9) expression. Serum levels of irisin are decreased in SAP patients. However, the role of irisin in BBB injury in SAP is still unknown. This study aimed to investigate whether irisin protects the BBB in SAP by affecting MMP-9 and its underlying regulatory mechanism.

Methods: An SAP model was established. Pancreatic injury was examined 24 h after SAP induction. Serum amylase and tumor necrosis factor-α (TNF-α) levels were examined by enzyme-linked immunosorbent assay (ELISA), and the brain water content was measured by the wet/dry proportion method. The structure and permeability of the BBB were examined by transmission electron microscopy, Evans blue exudation and transendothelial electrical resistance (TEER).

Results: In the brains of SAP rats, MMP-9 expression was increased, which was associated with damage to the BBB and the brain. Irisin inhibited this increase in MMP-9 and reduced brain edema and BBB permeability. The ERK/NF-κB axis is involved in irisin -mediated regulation of MMP-9. Irisin inhibited not only MMP-9 expression but also ERK/NF-κB phosphorylation. Furthermore, inhibiting ERK and NF-κB decreased MMP-9 levels and improved BBB dysfunction in SAP in vivo and in vitro. Moreover, irisin prevented the degradation of tight junctions (ZO-1, Claudin-5). The inhibition of ERK and NF-κB had similar effects on ZO-1 and Claudin-5 expression.

Conclusion: Irisin protects tight junctions and alleviates BBB dysfunction in SAP by inhibiting MMP-9 expression and regulates MMP-9 expression through ERK/NF-κB phosphorylation.