Transient Receptor Potential Vanilloid 1 Modulates Central Inflammation in Multiple Sclerosis.

Mario Stampanoni Bassi,Ennio Iezzi,Sara Zagaglia,Fabio Buttari,Antonietta Gentile,Girolama A Marfia,Annamaria Finardi,Ilaria Simonelli,Silvia Bullitta,Luana Gilio,Roberto Furlan,Georgia Mandolesi,Alessandra Musella,Livia Guadalupi,Diego Centonze

doi:10.3389/fneur.2019.00030

Abstract

Introduction: Disease course of multiple sclerosis (MS) is negatively influenced by proinflammatory molecules released by activated T and B lymphocytes and local immune cells. The endovanilloid system plays different physiological functions, and preclinical data suggest that transient receptor potential vanilloid type 1 (TRPV1) could modulate neuroinflammation in this disorder.Methods: The effect of TRPV1 activation on the release of two main proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-6, was explored in activated microglial cells. Furthermore, in a group of 132 MS patients, the association between the cerebrospinal fluid (CSF) levels of TNF and IL-6 and a single nucleotide polymorphisms (SNP) influencing TRPV1 protein expression and function (rs222747) was assessed.Results: In in vitro experiments, TRPV1 stimulation by capsaicin significantly reduced TNF and IL-6 release by activated microglial cells. Moreover, the anti-inflammatory effect of TRPV1 activation was confirmed by another TRPV1 agonist, the resiniferatoxin (RTX), whose effects were significantly inhibited by the TRPV1 antagonist, 5-iodoresiniferatoxin (5-IRTX). Vice versa, BV2 pre-treatment with 5-IRTX increased the inflammatory response induced by LPS. Moreover, in MS patients, a significant association emerged between TRPV1 SNP rs222747 and CSF TNF levels. In particular, the presence of a G allele, known to result in increased TRPV1 protein expression and function, was associated to lower CSF levels of TNF.Conclusions: Our results indicate that TRPV1 influences central inflammation in MS by regulating cytokine release by activated microglial cells. The modulation of the endovanilloid system may represent a useful approach to contrast neuroinflammation in MS.

Highlights

Disease course of multiple sclerosis (MS) is negatively influenced by proinflammatory molecules released by activated T and B lymphocytes and local immune cells
We investigated whether microglia might be involved in controlling neuroinflammation through TRPV1, using an in vitro experimental paradigm of microglia activation
TRPV1 activation did not alter per se the secretion of tumor necrosis factor (TNF) and IL-6 by BV2 cells at any of the concentrations used (10 and 25 μM) and the time points considered, i.e., short-term (6 h) and long-term (24 h) (Figure 1). At both time points, pre-stimulation of TRPV1 with 25 μM capsaicin significantly reduced the LPSinduced release of TNF and IL-6 by BV2 cells

Summary

Introduction

Disease course of multiple sclerosis (MS) is negatively influenced by proinflammatory molecules released by activated T and B lymphocytes and local immune cells. The endovanilloid system plays different physiological functions, and preclinical data suggest that transient receptor potential vanilloid type 1 (TRPV1) could modulate neuroinflammation in this disorder

Methods

Results

INTRODUCTION

RESULTS

DISCUSSION