Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis

Schroeder, J., Ross, K., McIntosh, K., Jabber, S., Woods, S., Crowe, J., Patterson Kane, J., Alexander, J., Lawrence, C. and Plevin, R. (2019) Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis. RMD Open, 5(1), e000711. (doi: 10.1136/rmdopen-2018-000711) (PMID:30713718) (PMCID:PMC6340532)

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.

• Item Type: Articles
• Additional Information: This study was funded by Wellcome Trust (WT089273MA).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Crowe, Dr Jenny and Lawrence, Dr Catherine and Schroeder, Dr Juliane and Ross, Dr Kirsty
• Authors: Schroeder, J., Ross, K., McIntosh, K., Jabber, S., Woods, S., Crowe, J., Patterson Kane, J., Alexander, J., Lawrence, C., and Plevin, R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: RMD Open
• Publisher: BMJ Publishing Group
• ISSN: 2056-5933
• ISSN (Online): 2056-5933
• Published Online: 11 January 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in RMD Open 5(1): e000711
• Publisher Policy: Reproduced under a Creative Commons License