Identification of atypical mitogen-activated protein kinase MAPK4 as a novel regulator in acute lung injury
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Cell & Bioscience Open Access
RESEARCH
Identification of atypical mitogen‑activated protein kinase MAPK4 as a novel regulator in acute lung injury Ling Mao1,2†, Ya Zhou1,3†, Longqing Chen1,2, Lin Hu1,2, Shiming Liu1,2, Wen Zheng4, Juanjuan Zhao1,2, Mengmeng Guo1,2, Chao Chen1,2, Zhixu He5,6* and Lin Xu1,2*
Abstract Background: 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. 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. Results: We 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 proinflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 knockdown using shRNA pretreatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions: Collectively, 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. Keywords: MAPK4, ALI, NFKB1, NR3C1, shRNA Background Acute lung injury (ALI) and it’s more serious form acute respiratory disease syndrome (ARDS) are critical diseases characterized with diffuse inflammations in lungs, which could be triggered by various pathologies, such as *Correspondence: [email protected]; [email protected] † Ling Mao and Ya Zhou contributed equally to this work 2 Department of Immunology, Zunyi Medical University, Zunyi 563003, Guizhou, China 5 Department of Paediatrics, Affiliated Hospital of Zunyi Medical University, Guizhou 563000, China Full list of author information is available at the end of the article
sepsis and severe trauma [1, 2]. Despite numerous therapeutic strategies have been used to ALI treatment [3–5], the worldwide incidence and mortality of ALI are still showing no sign of amelioration in the past decades [6, 7]. One of the reasons why these therapeutic strategies invalid is that the molecule mechanism of development of ALI is very complex and remains
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