Novel Protective Role For Map Kinase Phosphatase 2 In Inflammatory Arthritis

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 MKP2 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-alpha, 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-alpha 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.