Identification of atypical mitogen-activated protein kinase MAPK4 as a novel regulator in acute lung injury

Ya Zhou,Mengmeng Guo,Ling Mao,Wen Zheng,Lin Hu,Longqing Chen,Shiming Liu,Chao Chen,Juanjuan Zhao,Lin Xu,Zhixu He

doi:10.1186/s13578-020-00484-2

Abstract

BackgroundAcute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model.ResultsWe found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4−/− mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 knockdown using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge.ConclusionsCollectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

Highlights

Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide
Mitogen activated protein kinases 4 (MAPK4) deficiency ameliorates the pathology of ALI To assess the possible role of MAPK4 in ALI, we utilized MAPK4−/− mice to establish LPS-induced murine ALI model according to our previous work [15]
We found that the expression of MAPK4 was up-regulated in the lung tissues of ALI mice

Summary

Introduction

Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. Wang et al further reported that MAPK4 overexpression could promote the progression of lung cancer, indicating MAPK4 is a potential target for lung cancer therapy [14]. These findings indicate that MAPK4 play important roles in the development of various types of diseases. Up to now, the potential role of MAPK4 in the lung related inflammatory diseases including ALI, remains largely unknown

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