Perineural Mast Cells Are Specifically Enriched in Pancreatic Neuritis and Neuropathic Pain in Pancreatic Cancer and Chronic Pancreatitis

Abstract

BackgroundPancreatic neuritis is a histopathological hallmark of pancreatic neuropathy and correlates to abdominal neuropathic pain sensation in pancreatic adenocarcinoma (PCa) and chronic pancreatitis (CP). However, inflammatory cell subtypes that compose pancreatic neuritis and their correlation to the neuropathic pain syndrome in PCa and CP are yet unknown.MethodsInflammatory cells within pancreatic neuritis lesions of patients with PCa (n = 20) and CP (n = 20) were immunolabeled and colorimetrically quantified with the pan-leukocyte marker CD45, with CD68 (macrophages), CD8 (cytotoxic T-lymphocytes), CD4 (T-helper cells), CD20 (B-lymphocytes), NCL-PC (plasma cells), neutrophil elastase, PRG2 (eosinophils), anti-mast cell (MC) tryptase and correlated to pain sensation. Perineural mast cell subtypes were analyzed by double immunolabeling with MC chymase. Expression and neural immunoreactivity of protease-activated receptor type 1 (PAR-1) and type 2 (PAR-2) were analyzed in PCa and CP and correlated to pain status of the patients.ResultsIn PCa and CP, nerves were predominantly infiltrated by cytotoxic T-lymphocytes (PCa: 35% of all perineural inflammatory cells, CP: 33%), macrophages (PCa: 39%, CP: 33%) and MC (PCa: 21%, CP: 27%). In both entities, neuropathic pain sensation was associated with a specific increase of perineural MC (PCa without pain: 14% vs. PCa with pain: 31%; CP without pain: 19% vs. CP with pain: 34%), not affecting the frequency of other inflammatory cell subtypes. The vast majority of these MC contained MC chymase. PAR-1 and PAR-2 expression did not correlate to the pain sensation of PCa and CP patients.ConclusionPancreatic neuritis in PC and CP is composed of cytotoxic T-lymphocytes, macrophages and MC. The specific enrichment of MC around intrapancreatic nerves in neuropathic pain due to PCa and CP suggests the presence of MC-induced visceral hypersensitivity in the pancreas. Therefore, pancreatic and enteric neuropathies seem to share a similar type of neuro-immune interaction in the generation of visceral pain.

Neural plasticity in pancreatitis and pancreatic cancer

“…24,28 In an analysis on the subsets of inflammatory cells in patients with pancreatic neuritis, we could identify CD8 + cytotoxic T cells, macrophages and mast cells as the three major immune cell subpopulations. 25 In addition, the presence of pain in chronic pancreatitis or pancreatic cancer was associated with a specific increase in the perineural proportion of mast cells; the proportions of macrophages or cytotoxic T cells were not associated with the presence of pain. 25 The pancreatic perineural mast cells in patients with chronic pancreatitis and/or pancreatic cancer exhibited more frequent expression of tryptase than chymase, suggesting the predominance of activated tryptase-containing mast cells (M T type) as opposed to mature and less active tryptase and chymase coexpressing mast cells (M TC type).…”

“…25 In addition, the presence of pain in chronic pancreatitis or pancreatic cancer was associated with a specific increase in the perineural proportion of mast cells; the proportions of macrophages or cytotoxic T cells were not associated with the presence of pain. 25 The pancreatic perineural mast cells in patients with chronic pancreatitis and/or pancreatic cancer exhibited more frequent expression of tryptase than chymase, suggesting the predominance of activated tryptase-containing mast cells (M T type) as opposed to mature and less active tryptase and chymase coexpressing mast cells (M TC type). 25 For several gastrointestinal disorders, mast cells are specifically encountered in their activated form around intra-organ nerve fibres and correlate positively with the degree of neuropathic pain.…”

“…In true pancreatic neuritis, immune cells in contact with nerves need to be clearly marked off from the remaining pancreatic tissue immune cell infiltrate. 25 In perineuritis (severity I), immune cells are merely localized around the perineurium, not extending between the nerve fibre bundles. In endoneuritis (severity II), inflammatory cells are encountered between the nerve fibres within the nerve trunk.…”

Pathogenesis and Treatment of Pain in Chronic Pancreatitis

“…Recently, immunophenotyping of perineural immune cells in pancreatic neuritis in CP revealed that these immune cell infiltrations are mainly composed of macrophages, cytotoxic T lymphocytes and mast cells. However, it was only mast cells, which were specifically enriched around intrapancreatic nerves of patients who had more severe pain (15). Indeed, mast cells are typically localized in proximity of peptidergic nerve fibers containing substance P (SP), calcitoningene-related-peptide (CGRP) and can secrete numerous neuro-excitatory agents including histamine, serotonin, NGF, and proteases including mast cell tryptase.…”

“…These agents can bind to their corresponding receptors on neurons (H1-4, 5HT-3, tyrosine-kinase-receptor A/TrkA, protease-activated-receptor-1/PAR-1) and hereby trigger pain and neuronal over-activation. Therefore, this recent evidence proposes that CP patients show mast-cell-induced hypersensitivity like patients with irritable bowel syndrome (IBS), ulcerative colitis, migraine or interstitial cystitis (15).…”