Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis

Research output: Contribution to journalArticle

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.
LanguageEnglish
Article numbere000711
Pagese000711
Number of pages9
JournalRMD Open
Volume5
Issue number1
DOIs
Publication statusPublished - 11 Jan 2019

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Mitogen-Activated Protein Kinase Phosphatases
Protein Phosphatase 2
Mitogen-Activated Protein Kinase 1
Phosphoric Monoester Hydrolases
Arthritis
Neutrophils
Chemotaxis
Cytokines
Interleukin-6
Tumor Necrosis Factor-alpha
Pathology
Wild Animals
Experimental Arthritis
Leukotriene B4
Antibodies
Chemokines
Joints
Macrophages
Phosphorylation
Phenotype

Keywords

  • arthritis
  • neutrophils
  • MAP Kinase

Cite this

@article{7d293e8a7edd4ea08d075654e85e44b4,
title = "Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis",
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.",
keywords = "arthritis, neutrophils, MAP Kinase",
author = "Juliane Schroeder and Kirsty Ross and Kathryn McIntosh and Jabbar, {Shilan Khayrula Jabbar} and Stuart Woods and Jenny Crowe and Patterson-Kane, {Janet C} and James Alexander and Catherine Lawrence and Robin Plevin",
year = "2019",
month = "1",
day = "11",
doi = "10.1136/rmdopen-2018-000711",
language = "English",
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Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis. / Schroeder, Juliane; Ross, Kirsty; McIntosh, Kathryn; Jabbar, Shilan Khayrula Jabbar; Woods, Stuart; Crowe, Jenny; Patterson-Kane, Janet C; Alexander, James; Lawrence, Catherine; Plevin, Robin.

Vol. 5, No. 1, e000711, 11.01.2019, p. e000711.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis

AU - Schroeder, Juliane

AU - Ross, Kirsty

AU - McIntosh, Kathryn

AU - Jabbar, Shilan Khayrula Jabbar

AU - Woods, Stuart

AU - Crowe, Jenny

AU - Patterson-Kane, Janet C

AU - Alexander, James

AU - Lawrence, Catherine

AU - Plevin, Robin

PY - 2019/1/11

Y1 - 2019/1/11

N2 - 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.

AB - 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.

KW - arthritis

KW - neutrophils

KW - MAP Kinase

U2 - 10.1136/rmdopen-2018-000711

DO - 10.1136/rmdopen-2018-000711

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VL - 5

SP - e000711

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M1 - e000711

ER -