Selective Inhibition of Soluble TNF Using Xpro1595 Relieves Pain and Attenuates Cerulein-induced Pancreatic Pathology in Mice, With a Possible Link to Central Pain Processing

Abstract

Treatment of acute pancreatitis remains a challenge, with therapy focused on supportive care and treatment of the inciting etiology. Individuals with pancreatitis may experience severe upper abdominal pain, although pain mechanisms in patients with pancreatitis are incompletely understood and likely multifactorial, with possible pain processing occurring in the central nervous system, a process known to be associated with the upregulation of inflammatory cytokines. Inflammation plays a prominent role in the induction of acute pancreatitis, with the inflammatory cytokine tumor necrosis factor (TNF) both exacerbating cell death, pro-inflammatory signaling and edema, as well as promoting reparative and restorative mechanisms. This duality of function can be explained by different forms of the TNF ligand preferentially activating different receptor subtypes, whereby the uncleaved transmembrane form of the ligand (tmTNF) preferentially activates TNFR2 promoting restorative functions, but once cleaved the soluble form of TNF (solTNF) preferentially activates TNFR1 promoting detrimental pathology. For this reason, the traditional TNF inhibitors that inhibit both TNFR1 and TNFR2 have shown modest success in patients, but come with numerous side-effects, including immunological dysfunction and heart failure. Therefore, we sought to assess the effect of a novel selective inhibitor of solTNF (XPro1595) on pancreatic pathology and associated neuropathic pain in a mouse model of acute pancreatitis, and observe its effect on an area of the brain (the hippocampus) known to play a role in neuropathic pain processing. XPro1595 administration began after the initial peak in serum amylase to maximize clinical relevance. Administration of XPro1595 prevented pancreatic immune cell infiltration, that subsequently prevented tissue disruption and acinar cell death. These improvements in pathology were associated with a significant reduction in mechanical hypersensitivity (neuropathic pain). XPro1595 treatment also prevented an increase in hippocampal astrocyte reactivity, that may be associated with the prevention of neuropathic pain in this mouse model. Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of cerulein-induced pancreatitis in mice, which provides support of its use in patients with pancreatitis. This is the first study of its kind to identify a possible connection between hippocampal and pancreatic pathology and warrants further investigation.