IL-17A neutralizing antibody regulates monosodium urate crystal-induced gouty inflammation

Research output: Contribution to journalArticle

Authors

  • Federica Raucci
  • Anella Saviano
  • Paola Minosi
  • Marialuisa Piccolo
  • Carlo Irace
  • Francesco Caso
  • Raffaele Scarpa
  • Stefano Pieretti
  • Nicola Mascolo
  • Francesco Maione

Colleges, School and Institutes

External organisations

  • Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy.
  • Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
  • National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
  • Rheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy.
  • Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy. Electronic address: francesco.maione@unina.it.

Abstract

Gout is a paradigm of acute, self-limiting inflammation caused by the deposition of monosodium urate (MSU) crystals within intra-and/or peri-articular areas, leading to excruciating pain, joint swelling and stiffness. The infiltration of leukocytes drives the inflammatory response and remains an attractive target for therapeutic intervention. In this context, emerging evidence supports the view that systemic differentiation of Th17 cells and their in situ infiltration as one of the potential mechanisms by which these cells, and their main product IL-17, causes damage to target tissues. To test if IL-17 was having a detrimental role in gouty onset and progression we targeted this cytokine, using a neutralizing antibody strategy, in an experimental model of gout. Joint inflammation was induced in CD-1 mice by the intra-articular (i.a.) administration of MSU crystals (200 μg/20 μl). Animals from IL-17Ab-treated groups received 1, 3 and 10 μg (i.a.) in 20 μl of neutralizing antibody after MSU crystals administration. Thereafter, joints were scored macroscopically, and knee joint oedema determined with a caliper. Histological analysis, myeloperoxidase assay and western blots analysis for COX-2/mPGEs-1/IL-17R pathway were conducted at 18 h (peak of inflammation) to evaluate leukocytes infiltration and activation, followed by the analysis, in situ, of pro/anti-inflammatory cytokines and chemokines. Flow cytometry was also used to evaluate the modulation of infiltrated inflammatory monocytes and systemic Th17 and Treg profile. Treatment with IL-17Ab revealed a dose-dependent reduction of joint inflammation scores with maximal inhibition at 10 μg. The neutralizing antibody was also able to significantly reduce leukocytes infiltration and MPO activity as well the expression of JE, IL-1α, IL-1β, IL-16, IL-17, C5a, BLC and, with a less extent IP-10, Rantes, KC, TIMP-1, SDF-1 and metalloproteinases in inflamed tissues. Biochemical analysis also revealed that IL-17Ab treatment modulated COX-2/mPGEs-1 pathway (and related PGE 2 production) without interfering with IL-17R expression. Furthermore, flow cytometry analysis highlighted a selective modulation of infiltrating inflammatory monocytes (B220 -/GR1 hi-F480 hi/CD115 +) and circulating Th17, but not Treg, cells after IL-17Ab treatment. Collectively the results of this study report for the first time, that i.a. injection of MSU crystals stimulates in vivo production of Th17 cells and Th17-related inflammatory cyto-chemokines. In addition, we have demonstrated that the administration of a neutralizing antibody against IL-17 attenuates joint symptoms, swelling and leukocytes infiltration to the inflamed tissue, possibly providing a new strategy for the treatment of gouty inflammation and/or arthritis.

Bibliographic note

Copyright © 2019 Elsevier Ltd. All rights reserved.

Details

Original languageEnglish
Article number104351
JournalPharmacological Research
Volume147
Early online date14 Jul 2019
Publication statusPublished - Sep 2019

Keywords

  • Ethanol (CID:702), Gout, IL-17A, Inflammation, Monosodium urate crystal, Neutralizing antibody, PGE2 (CID:5280360), Phosphate-buffered saline (CID: 24978514), Sodium chloride (CID:5234), Sodium urate (CID: 23697816)

ASJC Scopus subject areas