The impact of Fractalkine/CX3CR1 on the course and pain generation in experimental pancreatitis
Final Report Abstract
Acute and chronic pancreatitis are inflammatory diseases of the pancreas that are characterized by inflammatory cell infiltration and severe abdominal pain. Fractalkine is a chemokine that chemoattracts inflammatory cells through its highly selective receptor CX3CR1 and has been suggested to aggravate pancreatic inflammation and pain. Spinal cord microglia express CX3CR1 and have been shown to modulate pain in chronic pain states. We therefore aimed to investigate the course of acute and chronic cerulein pancreatitis in CX3CR1-/- mice and the potential therapeutic implications of CX3CR1 neutralization using a small molecule inhibitor. AP and CP was induced in CX3CR1-knockout and CX3CR1 small molecule inhibitor treated wild-type mice by repetitive intraperitoneal cerulein injections. Hyperalgesia was assessed by systematic behavioral observation, locomotion analysis, and measurement of abdominal mechanical sensitivity. Pancreatic and spinal cord tissue was harvested after sacrifice for further analyses. Pathomorphological severity of both AP and CP in CX3CR1-/- mice vs. wild-type controls was comparable. However, CX3CR1 small molecule inhibitor treated mice showed an attenuated AP with significantly less pancreatic inflammatory cell infiltration. Notably, this was not the case in chronic pancreatitis. In both AP and CP all knockout/treated mice showed significantly less pain related behaviour (p < 0.0001) with a clear dose-response correlation in the treatment arms in AP. In AP, intrapancreatic IL6 and MCP-1 levels were lower in small molecule inhibited mice when compared to untreated controls. On the spinal level, small molecule inhibitor treated mice showed a dose-dependent decrease of microglial activation measured by Iba-1 and p-p38 immunohistochemistry. We therefore conclude that fractalkine signaling seems to be crucial in initiating and maintaining pancreatic hyperalgesia in pancreatitis. In acute pancreatitis this seems to be by aggravating local inflammatory reaction and activating spinal cord microglia via the highly selective receptor CX3CR1. Therefore, these novel findings reveal CX3CR1 as a promising new target for the treatment of acute pancreatitis and chronic pancreatic pain.
