Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Abstract

The chemokine fractalkine induces migration of inflammatory cells into inflamed tissues, thereby aggravating inflammatory tissue damage and fibrosis. Furthermore, fractalkine increases neuropathic pain through glial activation, which can be diminished by blocking of its receptor, CX3CR1, through neutralizing antibodies. As chronic pancreatitis (CP) is characterized by tissue infiltration of inflammatory cells, fibrosis, pancreatic neuritis and severe pain, the roles of fractalkine and CX3CR1 were investigated in CP (n ¼ 61) and normal pancreas (NP, n ¼ 21) by QRT-PCR, western blot and immunohistochemistry analyses. Their expression correlated with the severity of pancreatic neuritis, fibrosis, intrapancreatic nerve fiber density and hypertrophy, pain, CP duration and with the amount of inflammatory cell infiltrate immuno-positive for CD45 and CD68. To investigate the influence of fractalkine on pancreatic fibrogenesis, human pancreatic stellate cells (hPSCs) were isolated from patients with CP, incubated with fractalkine and then Collagen-1 and a-smooth muscle actin (a-SMA) expressions were measured. CX3CR1, but not fractalkine, mRNA was overexpressed in CP. In contrast, the protein levels of both CX3CR1 and fractalkine were upregulated. Neuro-immunoreactivity for fractalkine and CX3CR1 was strongest in patients suffering from severe pain and pancreatic neuritis. Long-term suffering from CP was noticeably related to increased neural immunoreactivity of fractalkine. Furthermore, fractalkine and CX3CR1 mRNA overexpressions were associated with enhanced lymphocyte and macrophage infiltration. Advanced fibrosis was associated with increased fractalkine expression, whereas in vitro fractalkine had no significant impact on collagen-1 and a-SMA expressions in hPSCs. Therefore, pancreatic fractalkine expression appears to be linked to visceral pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However, pancreatic fibrogenesis is probably indirectly influenced by fractalkine. Taken together, these novel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduce inflammation and modulate pain in CP.

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells

“…This result supported previous study results and indicated that pancreatic tissue injury and various environmental factors promote CX3CL1 expression in the whole pancreas, so that connection of membrane-bound CX3CL1 and CX3CL1 receptors of inflammatory cells in the pancreatic tissue serves as the basis of the inflammation in CP as it does in chronic hepatitis. 11,17,18,36,37 Furthermore, sheddase is essential for CX3CL1 secretion into the blood. The abundant expression of sheddase in PSCs, as in hepatic stellate cells, 34 indicates that MMP not only enhances extracellular matrix degradation but also induces inflammation by CX3CL1 secretion.…”

“…17 Increased expression of CX3CL1 in pancreatic tissue in human CP has also been correlated with pain scores. 18 As excessive expression and secretion of CX3CL1 has also been observed in patients with rheumatoid arthritis, arteriosclerosis, cardiovascular diseases, HIV infection, nephritis, and neuropathic pain, [19][20][21][22][23][24][25][26][27] it has naturally attracted attention as a potential target of treatment for inflammatory diseases. 28,29 Here, we report new results concerning possible mechanisms of the increase in serum concentrations of CX3CL1, which is associated with fibrosis and pain in patients with alcoholic CP, using culture-activated PSCs.…”

Fate of nerves in chronic pancreatitis: Neural remodeling and pancreatic neuropathy

“…In addition to this potential role in pancreatic neuritis, also the infiltration of the whole pancreatic tissue by lymphocytes and macrophages strongly correlated with fractalkine and CX3CR1 mRNA overexpression. Although advanced fibrosis was associated with increased fractalkine expression, in vitro fractalkine had no effect upon on collagen-1 and alpha-SMA expression in human pancreatic stellate cells (hPSCs), suggesting a primarily indirect involvement of fractalkine in fibrosis in CP [22]. However, it was obvious that pancreatic fractalkine expression is closely related to visceral neuropathic pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with resulting pancreatic neuritis (Fig.…”

“…In a recent study, we identified one of the molecular factors that could potentially induce migration of inflammatory cells into the surrounding of nerves and contribute to increased pain sensation: the chemokine fractalkine [22]. Due to its ability to induce immune cell migration, neuropathic pain via glial activiation and its well-established role in fibrogenesis, fractalkine and its receptor CX3CR1 were ideal candidates to study in the context of CP.…”

Pathogenesis and Treatment of Pain in Chronic Pancreatitis

“…The tissue levels of nerve growth factor (NGF) and the glial-cell-line-derived neurotrophic factor family member artemin and neurturin in CP tissues have been demonstrated to correlate to the extent of neural hypertrophy and the degree of pain sensation in these patients (9,31). Similarly, overexpression of the neuronal chemokine fractalkine in CP tissues and pancreatic nerves is known to correlate to pancreatic neuritis, and to the severity and duration of the pain syndrome in CP (12). However, the study of these morphological alterations in a functional manner is limited by the still ongoing lack of animal models that exhibit similar neuroplastic-neuropathic alterations.…”