Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis

ObjectivesWe 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.MethodsTo achie...

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Published in:	Rheumatic & musculoskeletal diseases open Vol. 5; no. 1; p. e000711
Main Authors:	Schroeder, Juliane, Ross, Kirsty, McIntosh, Kathryn, Jabber, Shilan, Woods, Stuart, Crowe, Jenny, Patterson Kane, Janet, Alexander, James, Lawrence, Catherine, Plevin, Robin
Format:	Journal Article
Language:	English
Published:	England EULAR 01-01-2019 BMJ Publishing Group LTD BMJ Publishing Group
Series:	Original article
Subjects:	Animal Models Animals Apoptosis arthritis Arthritis - etiology Arthritis - metabolism Arthritis - pathology Arthritis, Experimental chemokines Collagen Cytokines Cytokines - metabolism Disease Disease Models, Animal Disease Susceptibility Genetic Association Studies Infections Inflammation Inflammation Mediators - metabolism Kinases Male Mice Mice, Knockout Neutrophils Optical Imaging - methods Pathogenesis Phosphatase Protein Tyrosine Phosphatases - genetics Protein Tyrosine Phosphatases - metabolism Proteins Rheumatoid arthritis Rodents Studies United Kingdom > UK arthritis chemokines inflammation
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Summary:	ObjectivesWe 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.MethodsTo 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.ResultsMKP-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.ConclusionsThis is the first study to show a protective role for MKP-2 in inflammatory arthritis.
Bibliography:	Original article ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2056-5933 2056-5933
DOI:	10.1136/rmdopen-2018-000711