MK2 Is Required for Neutrophil-Derived ROS Production and Inflammatory Bowel Disease.

Tao Zhang,Wenjuan Zhao,Lu Xu,Junhang Jiang,Feng Qian,Shixin Duan,Lei Sun,Jingting Liu

doi:10.3389/fmed.2020.00207

Tao Zhang, Wenjuan Zhao + Show 6 more

Open Access

https://doi.org/10.3389/fmed.2020.00207

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Abstract

Inflammatory bowel disease (IBD) is a chronic disease that is commonly accompanied by increased inflammatory responses and elevated reactive oxygen species (ROS) of the gastrointestinal tract. Here, we found that MAPK-activated protein kinase 2 (MK2) modulates ROS production and is required for dextran sulfate sodium (DSS)-induced IBD in the mouse model. Genetic ablation of MK2 in the myeloid lineage cells (MK2Lyz2−KO) protected against DSS-induced colitis injury. In response to DSS challenge, compared to MK2lyz2−WT mice, MK2Lyz2−KO mice exhibited less damage of epithelial and goblet cells, decreased generation of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and ROS, as well as reduced Ki67-positive cells and concentrations of myeloperoxidase (MPO) in the intestinal epithelium. Furthermore, upon treatment with formylated peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF), the generation of ROS was attenuated in MK2-deficient neutrophils, in which the phosphorylation of Akt and p38 MAPK was also reduced. Collectively, these findings indicated that MK2 is required for neutrophil-derived ROS production and IBD, and MK2 and ROS are promising therapeutic targets for IBD.

Highlights

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by chronic uncontrolled intestinal inflammation [1]
Together with our previous findings, these results suggested that MAPK-activated protein kinase 2 (MK2) was required for formylated peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF)-induced activation of Akt, p38 MAPK, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neutrophils, and MK2 ablation in the myeloid lineage cells had a negative impact on the activation of Akt, p38 MAPK, and NADPH oxidase, resulting in the reduction of reactive oxygen species (ROS) production by neutrophils, alleviating IBD
We found that MK2 modulated neutrophil-derived ROS production and was required for DSSinduced IBD

Summary

INTRODUCTION

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by chronic uncontrolled intestinal inflammation [1]. During the process of IBD, activated immune cells secrete amounts of inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β,IL-6, and reactive oxygen species (ROS) [1, 8]. Accumulating data from both experimental animal models. Upon treatment with N-formyl-methionyl-leucylphenylalanine (fMLF), the generation of ROS was attenuated in MK2 deficient neutrophils, in which the phosphorylation of Akt and p38 MAPK was reduced These findings indicated that MK2 was required for neutrophil-derived ROS production and IBD, and MK2 and ROS were promising therapeutic targets for IBD

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RESULTS

DISCUSSION