Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis
Autor: | James Alexander, Juliane Schroeder, Stuart Woods, Robin Plevin, Kirsty Ross, Janet Patterson Kane, Kathryn McIntosh, Jenny Crowe, Shilan Jabber, Catherine E. Lawrence |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine Chemokine Leukotriene B4 Inflammatory arthritis Immunology Arthritis Inflammation chemokines Proinflammatory cytokine RS Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Rheumatology Animals Immunology and Allergy Medicine Genetic Association Studies Mice Knockout biology business.industry Optical Imaging Wild type Chemotaxis Animal Models medicine.disease Arthritis Experimental 3. Good health Disease Models Animal 030104 developmental biology chemistry arthritis inflammation 030220 oncology & carcinogenesis biology.protein Cytokines Disease Susceptibility Inflammation Mediators Protein Tyrosine Phosphatases medicine.symptom business |
Zdroj: | RMD Open |
ISSN: | 2056-5933 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |