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 To ach...
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| Language: | English |
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BMJ Publishing Group
2019-06-01
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| Series: | RMD Open |
| Online Access: | https://rmdopen.bmj.com/content/5/1/e000711.full |
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| author | Juliane Schroeder Kirsty Ross Kathryn McIntosh Shilan Jabber Stuart Woods Jenny Crowe Janet Patterson Kane James Alexander Catherine Lawrence Robin Plevin |
| author_facet | Juliane Schroeder Kirsty Ross Kathryn McIntosh Shilan Jabber Stuart Woods Jenny Crowe Janet Patterson Kane James Alexander Catherine Lawrence Robin Plevin |
| author_sort | Juliane Schroeder |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-af16d99b350249eca6ff4e9b3973b3d3 |
| institution | Kabale University |
| issn | 2056-5933 |
| language | English |
| publishDate | 2019-06-01 |
| publisher | BMJ Publishing Group |
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| series | RMD Open |
| spelling | doaj-art-af16d99b350249eca6ff4e9b3973b3d32025-08-20T03:50:44ZengBMJ Publishing GroupRMD Open2056-59332019-06-015110.1136/rmdopen-2018-000711Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritisJuliane Schroeder0Kirsty Ross1Kathryn McIntosh2Shilan Jabber3Stuart Woods4Jenny Crowe5Janet Patterson Kane6James Alexander7Catherine Lawrence8Robin Plevin91 Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland2 Pure and Applied Chemistry, Technology Innovation Centre, University of Strathclyde, Glasgow, Scotland3 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland3 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland3 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland1 Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland4 Flagship Biosciences Inc, Massey University, Denver, Colorado, USA3 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland3 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland3 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, ScotlandObjectives 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.https://rmdopen.bmj.com/content/5/1/e000711.full |
| spellingShingle | Juliane Schroeder Kirsty Ross Kathryn McIntosh Shilan Jabber Stuart Woods Jenny Crowe Janet Patterson Kane James Alexander Catherine Lawrence Robin Plevin Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis RMD Open |
| title | Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis |
| title_full | Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis |
| title_fullStr | Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis |
| title_full_unstemmed | Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis |
| title_short | Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis |
| title_sort | novel protective role for map kinase phosphatase 2 in inflammatory arthritis |
| url | https://rmdopen.bmj.com/content/5/1/e000711.full |
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