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Animal models
Original article
Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis
  1. Juliane Schroeder1,
  2. Kirsty Ross2,
  3. Kathryn McIntosh3,
  4. Shilan Jabber3,
  5. Stuart Woods3,
  6. Jenny Crowe1,
  7. Janet Patterson Kane4,
  8. James Alexander3,
  9. Catherine Lawrence3 and
  10. Robin Plevin3
  1. 1 Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland
  2. 2 Pure and Applied Chemistry, Technology Innovation Centre, University of Strathclyde, Glasgow, Scotland
  3. 3 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland
  4. 4 Flagship Biosciences Inc, Massey University, Denver, Colorado, USA
  1. Correspondence to Dr Robin Plevin; r.plevin{at}strath.ac.uk

Abstract

Objectives We have previously shown mitogen-activated protein kinase phosphatase 2 (MKP-2) to be a key regulator of proinflammatory cytokines in macrophages. In the study presented here, we investigated the role of MKP-2 in inflammatory arthritis with a particular focus on neutrophils.

Methods To achieve this, we subjected MKP-2 deficient and wild type mice to collagen antibody induced arthritis, an innate model of arthritis, and determined disease pathology. To further our investigation, we depleted neutrophils in a prophylactic and therapeutic fashion. Last, we used chemotaxis assays to analyse the impact of MKP-2 deletion on neutrophil migration.

Results MKP-2-/- mice showed a significant increase in disease pathology linked to elevated levels of proarthritic cytokines and chemokines TNF-α, IL-6 and MCP-1 in comparison to wild type controls. This phenotype is prevented or abolished after administration of neutrophil depleting antibody prior or after onset of disease, respectively. While MCP-1 levels were not affected, neutrophil depletion diminished TNF-α and reduced IL-6, thus linking these cytokines to neutrophils. In vivo imaging showed that MKP-2-/- mice had an increased influx of neutrophils into affected joints, which was higher and potentially prolonged than in wild type animals. Furthermore, using chemotaxis assays we revealed that MKP-2 deficient neutrophils migrate faster towards a Leukotriene B4 gradient. This process correlated with a reduced phosphorylation of ERK in MKP-2-/- neutrophils.

Conclusions This is the first study to show a protective role for MKP-2 in inflammatory arthritis.

  • arthritis
  • inflammation
  • chemokines

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: http://creativecommons.org/licenses/by/4.0

https://doi.org/10.1136/rmdopen-2018-000711

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    Footnotes

    • Contributors All authors contributed to this manuscript, with experimental design, execution of experiments, data analysis and manuscript preparation.

    • Funding This study was funded by Wellcome Trust (WT089273MA).

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval University of Strathclyde, home office approval and local ethical committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All data generated during this study have been included either in the main manuscript or as supplemental figures.