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

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 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. 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.

Epigenome-wide association study and epigenetic age acceleration associated with cigarette smoking among Costa Rican adults

“…Four of these sites were hypomethylated and annotated to the MAPK4 , HNRNPM , and PTGIR genes. MAPK4 is an atypical kinase involved with the AKT/mTOR signaling pathway, and overexpression is associated with acute lung injury and cancers 63 , 64 . Similarly, the HNRNPM and PTGIR proteins have been shown to promote cancerous cell growth and be associated with poorer oncogenic outcomes 65 , 66 .…”

Epigenetics and stroke: role of DNA methylation and effect of aging on blood–brain barrier recovery

“…Furthermore, hypomethylation within the exons of the ephrin type-A receptor ( Epha2 ) is reported to mediate brain endothelial cell TJ disruption in inflammatory conditions [ 75 ]. Other unfavorable factors for BBB recovery are the activation of the Rho GTPase RhoA and CDC42 effector protein 4 ( Cdc42ep4 ), both indicated in regulating actin remodeling, stress fiber formation, and TJ complex disassembly, as well as atypical Map kinase Mapk4 , the overexpression of which shifts cells to a proinflammatory phenotype [ 76 – 79 ]. Presumably, the balance, or lack thereof, between favorable and unfavorable processes/factors may predict the final outcomes of BBB poststroke recovery.…”

Potential role of LPAR5 gene in prognosis and immunity of thyroid papillary carcinoma and pan-cancer

“…Therefore, whether there is a certain connection between LPAR5 and LIPH through certain media is worth further exploration. MAPK4 is an atypical MAPK involved in the development of many human diseases 23 , 24 . Wang et al demonstrated that MAPK4 promotes cancer progression by stimulating the AKT/mTOR signaling pathway, which is closely related to cell growth, survival, metastasis, metabolism, etc 25 .…”