Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia

Giovanni Sarnelli, Marcella Pesce, Luisa Seguella, Jie Lu, Eleonora Efficie, Jan Tack, Fatima Domenica Elisa De Palma, Alessandra D'Alessandro, Giuseppe Esposito, Giovanni Sarnelli, Marcella Pesce, Luisa Seguella, Jie Lu, Eleonora Efficie, Jan Tack, Fatima Domenica Elisa De Palma, Alessandra D'Alessandro, Giuseppe Esposito

Abstract

Background & aims: Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been investigated systematically. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has not been assessed.

Methods: Duodenal biopsy specimens from FD and control subjects, and peroxisome proliferator-activated receptor-α (PPARα) null mice were cultured at a pH of 3.0 and 7.4. Mast cell (MC) number, the release of their mediators, and the expression of transient receptor potential vanilloid receptor (TRPV)1 and TRPV4, were evaluated. All measurements also were performed in the presence of a selective blocker of neuronal action potential (tetradotoxin). FD and control biopsy specimens in acidified medium also were incubated in the presence of different PEA concentrations, alone or combined with a selective PPARα or PPAR-γ antagonist.

Results: An acid-induced increase in MC density and the release of their mediators were observed in both dyspeptic patients and controls; however, this response was amplified significantly in FD. This effect was mediated by submucosal nerve fibers and up-regulation of TRPV1 and TRPV4 receptors because pretreatment with tetradotoxin significantly reduced MC infiltration. The acid-induced endogenous release of PEA was impaired in FD and its exogenous administration counteracts MC activation and TRPV up-regulation.

Conclusions: Duodenal acid exposure initiates a cascade of neuronal-mediated events culminating in MC activation and TRPV overexpression. These phenomena are consequences of an impaired release of endogenous PEA. PEA might be regarded as an attractive therapeutic strategy for the treatment of FD.

Keywords: Duodenal Mucosa; Enteric Nervous System; Functional Dyspepsia; Mast Cells; Visceral Hypersensitivity.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Effects of acid challenge on mucosal MC numbers and activation. (A) Histochemical images showing toluidine-positive cells (arrows) and (B) relative quantification of MCs in duodenal mucosa of dyspeptic and control biopsy specimens cultured at pH 3.0 and 7.4, respectively, and in the presence or absence of TTX. Original magnification: 20×. Data show the number of MCs counted per square millimeter of tissue. (C) Representative immunofluorescence images showing the close proximity of tryptase-immunoreactive cells (red) to NeuN-positive fibers (green). Original magnification: 20×. (D) Relative quantification of tryptase-immunopositive cells. Data show the number of tryptase-positive cells per square millimeter of tissue. (E–H) ELISA assays, respectively, quantifying the release of tryptase, histamine, NGF, and PGD2 in FD and healthy duodenal mucosal biopsy specimens. ∗∗∗P < .001 vs control; °°°P < .001 FD untreated vs pretreatment with TTX; #P < .05 control untreated vs pretreatment with TTX. All results are expressed as means ± SD of 20; n = 20 and 10 (B and D) and 10 and 6 (F–H) dyspeptic and control subjects, respectively.
Figure 2
Figure 2
Acid challenge up-regulates TRPV1 and TRPV4 expression in submucosal nerve endings. (A) Immunofluorescence staining of NeuN (green) and TRPV1-positive cells (red), and (B) relative graph bars quantifying TRPV1-positive cells in duodenal mucosa of dyspeptic and controls biopsy specimens cultured at pH 3.0 and 7.4, respectively, and in the presence or absence of TTX. Original magnification: 20×. Data show the number of TRPV1-positive cells per square millimeter of tissue. (C) Immunoblot analysis and relative densitometric analysis (arbitrary units normalized on the expression of the housekeeping protein β-actin) quantifying TRPV1 protein expression. (D) Immunofluorescence staining and (E) relative graph bars quantifying TRPV4-positive cells (red). Original magnification: 20×. Data show the number of TRPV4-positive cells per square millimeter of tissue. (F) Immunoblot analysis and relative densitometric analysis (arbitrary units normalized on the expression of the housekeeping protein β-actin) quantifying TRPV4 protein expression. ∗∗∗P < .001 vs control; °°°P < .001 FD untreated vs pretreatment with TTX and #P < .05 control untreated vs pretreatment with TTX. All results are expressed as means ± SD of 20; n = 20 and 10 (B and E) and 10 and 6 (C and F) dyspeptic and control subjects, respectively. OD, optical density.
Figure 3
Figure 3
Acid-induced release of PEA and PPARα expression in duodenal mucosa. (A) Representative chromatography coupled to tandem mass spectrometry analysis and (B) relative quantification of PEA levels (expressed as nanomolar concentration in duodenal homogenates) from mucosa of 20 dyspeptic and 10 control biopsy specimens cultured at pH 3.0 and 7.4, respectively, and in the presence or absence of TTX. (C) Immunoblot analysis and relative densitometric analysis (arbitrary units normalized on the expression of the housekeeping protein β-actin) showing PPARα protein expression in tissue homogenates from 10 and 6 dyspeptic and control subjects, respectively. ∗∗∗P < .001 vs control; °P < .05 FD untreated vs pretreatment with TTX; ###P < .05 control untreated vs pretreatment with TTX. All results are expressed as means ± SD.
Figure 4
Figure 4
Effects of exogenous PEA administration on acid-induced MC recruitment, TRPV1 and TRPV4 expression, and inflammatory mediator release in duodenal mucosa from dyspeptic patients. (A) Immunohistochemical images showing toluidine-positive cells (arrows) and (B) relative quantification of MCs in duodenal mucosa deriving from dyspeptic patient cultured biopsy specimens at (1) pH = 3.0, in the presence of (2) exogenous PEA (0.1 μmol/L), co-incubated with either (3) PPARα antagonist MK866 (3 μmol/L), or (4) PPARγ antagonist (GW9662 9 nmol/L). Original magnification: 20×. Data show the number of MCs counted per square millimeter of tissue. Immunofluorescence staining of NeuN (green) and (C) tryptase-, (E) TRPV1-, (G) TRPV4-positive cells (all red) and relative graph bars quantifying (D) tryptase-positive, (F) TRPV1-positive, (H) and TRPV4-positive cells. Data show the number of immune-reactive cells counted per square millimeter of tissue. Original magnification: 20×. (I) Immunoblot analysis and relative densitometric analysis (arbitrary units normalized on the expression of the housekeeping protein β-actin) quantifying (J) TRPV1 and (K) TRPV4 protein expression at (1) pH = 3.0, in the presence of increasing concentrations of exogenous PEA (2) 0.001 μmol/L, (3) 0.01 μmol/L, (4) 0.1 μmol/L alone, or co-incubated with either (5) PPARα antagonist MK866 (3 μmol/L) or (6) PPARγ antagonist (GW9662 9 nmol/L). (L–O) ELISA essays quantifying, respectively, the release of tryptase, NGF (pg/mL), histamine, and PGD2 in dyspeptic biopsy specimens, cultured in the same experimental conditions. ∗P < .05 for PEA 0.001 μmol/L, ∗∗P < .01 for PEA 0.01 μmol/L, and ∗∗∗P < .001 for PEA 0.1 μmol/L vs acid challenge and for co-incubation with PPARγ antagonist GW9662 vs acid challenge; °°°P < .001 for co-incubation with PPARα antagonist MK866 vs acid challenge. All results are means ± SD of n = 20 dyspeptic subjects.
Figure 5
Figure 5
Effects of increasing concentrations of exogenous PEA in in vitro duodenal biopsy specimens from controls. (A) Immunohistochemical images showing toluidine-positive cells (arrows) and (B) relative quantification of MCs in duodenal mucosa deriving from control cultured biopsy specimens at (1) pH = 3.0, in the presence of (2) exogenous PEA (0.1 μmol/L), co-incubated with either (3) PPARα antagonist MK866 (3 μmol/L) or (4) PPARγ antagonist (GW9662 9 nmol/L). Original magnification: 20×. Data show the number of MCs counted per square millimeter of tissue. Immunofluorescence staining of NeuN (green) and (C) tryptase-positive, (E) TRPV1-positive, and (G) TRPV4-positive cells (all red) and relative graph bars quantifying (D) tryptase-positive, (F) TRPV1-positive, (H) and TRPV4-positive cells deriving from controls biopsy specimens, cultured in the same experimental conditions. Original magnification: 20×. Data show the number of immune-reactive cells counted per square millimeter of tissue. (I) Immunoblot analysis and relative densitometric analysis (arbitrary units normalized on the expression of the housekeeping protein β-actin) quantifying (J) TRPV1 and (K) TRPV4 protein expression in tissue homogenates deriving from control cultured biopsy specimens at (1) pH = 3.0, in the presence of increasing concentrations of exogenous PEA (2) 0.001 μmol/L, (3) 0.01 μmol/L, (4) 0.1 μmol/L alone or co-incubated with either (5) PPARα antagonist MK866 (3 μmol/L) or (6) PPARγ antagonist (GW9662 9 nmol/L). (L–O) ELISA essays quantifying, respectively, the release of tryptase, NGF, histamine, and PGD2 in dyspeptic biopsy specimens, cultured in the same experimental conditions. ∗P < .05 for PEA 0.001 μmol/L, ∗∗P < .01 for PEA 0.01 μmol/L, and ∗∗∗P < .001 for PEA 0.1 μmol/L vs acid challenge and for co-incubation with PPARγ antagonist GW9662 vs acid challenge; °°°P < .001 for co-incubation with PPARα antagonist MK866 vs acid challenge. All results are means ± SD of n = 10 control subjects.
Figure 6
Figure 6
Effects of acid challenge and exogenous PEA administration in PPARα KO mice. (A) Histochemical images showing toluidine-positive cells (arrows) and (B) relative quantification of MCs in the duodenum of PPARα KO mice at pH 3.0 and 7.4, in the presence or absence of exogenous PEA 10 μmol/L. Original magnification: 20×. Data show the number of MCs counted per square millimeter of tissue. Immunofluorescence staining of NeuN (green) and (C) tryptase-positive, (E) TRPV1-positive, and (G) TRPV4-positive cells (all red) and relative graph bars quantifying (D) tryptase-positive, (F) TRPV1-positive, (H) and TRPV4-positive cells deriving from PPARα KO mice in the same experimental conditions. Original magnification: 20×. Data show the number of immune-reactive cells counted per square millimeter of tissue. (I) Immunoblot analysis and relative densitometric analysis (arbitrary units normalized on the expression of the housekeeping protein β-actin) quantifying (J) TRPV1 and (K) TRPV4 protein expression. (L–O) ELISA essays quantifying, respectively, the release of tryptase, NGF, histamine, and PGD2 in PPARα KO mice, in the same experimental conditions. All results are the means ± SD of n = 10 mice for each experimental group, respectively. ∗∗∗P < .001 vs acid challenge.

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