Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis
Schroeder, Juliane and Ross, Kirsty and McIntosh, Kathryn and Jabbar, Shilan Khayrula Jabbar and Woods, Stuart and Crowe, Jenny and Patterson-Kane, Janet C and Alexander, James and Lawrence, Catherine and Plevin, Robin (2019) Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis. RMD Open, 5 (1). e000711. e000711. ISSN 2056-5933 (https://doi.org/10.1136/rmdopen-2018-000711)
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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: T o 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: T his is the first study to show a protective role for MKP-2 in inflammatory arthritis.
ORCID iDs
Schroeder, Juliane, Ross, Kirsty ORCID: https://orcid.org/0000-0003-4751-3287, McIntosh, Kathryn ORCID: https://orcid.org/0000-0003-0222-3585, Jabbar, Shilan Khayrula Jabbar ORCID: https://orcid.org/0000-0001-6908-0043, Woods, Stuart ORCID: https://orcid.org/0000-0002-3798-2074, Crowe, Jenny, Patterson-Kane, Janet C, Alexander, James, Lawrence, Catherine ORCID: https://orcid.org/0000-0001-9928-8451 and Plevin, Robin ORCID: https://orcid.org/0000-0002-7849-1220;-
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Item type: Article ID code: 66560 Dates: DateEvent11 January 2019Published25 November 2018AcceptedSubjects: Medicine > Pharmacy and materia medica Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Depositing user: Pure Administrator Date deposited: 14 Jan 2019 16:52 Last modified: 31 Oct 2024 01:46 URI: https://strathprints.strath.ac.uk/id/eprint/66560