miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury

Abstract

Sepsis and acute lung injury (ALI) are linked to mitochondrial dysfunction; however, the underlying mechanism remains elusive. We previously reported that c-Jun N-terminal protein kinase 2 (JNK2) promotes stress-induced mitophagy by targeting small mitochondrial alternative reading frame (smARF) for ubiquitin-mediated proteasomal degradation, thereby preventing mitochondrial dysfunction and restraining inflammasome activation. Here we report that loss of JNK2 exacerbates lung inflammation and injury during sepsis and ALI in mice. JNK2 is downregulated in mice with endotoxic shock or ALI, concomitantly correlated inversely with disease severity. Small RNA sequencing revealed that miR-221-5p, which contains seed sequence matching to JNK2 mRNA 3’ untranslated region (3’UTR), is upregulated in response to lipopolysaccharide, with dynamically inverse correlation with JNK2 mRNA levels. miR-221-5p targets the 3’UTR of JNK2 mRNA leading to its downregulation. Accordingly, miR-221-5p exacerbates lung inflammation and injury during sepsis in mice by targeting JNK2. Importantly, in patients with pneumonia in medical intensive care unit, JNK2 mRNA levels in alveolar macrophages flow sorted from non-bronchoscopic broncholaveolar lavage (BAL) fluid were inversely correlated strongly and significantly with the percentage of neutrophils, neutrophil and white blood cell counts in BAL fluid. Our data suggest that miR-221-5p targets JNK2 and thereby aggravates lung inflammation and injury during sepsis.

Mogroside V alleviates inflammation response by modulating miR-21-5P/SPRY1 axis

“…Numerous studies have shown that microRNAs take part in various physiological and pathological processes, and their abnormal expression profiles regulate different kinds of diseases, including lung inflammation, 30 so they are recognized as vital diagnosis or treatment biomarkers. 31 miR-21 is usually high expressed in many diseases, and has been regarded as a key mediator in the inflammatory response. 32 miR-21-5p, as a member of the miR-21 family, has been reported to play an important role in cell apoptosis, pathological growth, and inflammation.…”

Gene expression profile of mitogen-activated kinases and microRNAs controlling their expression in HaCaT cell culture treated with lipopolysaccharide A and cyclosporine A

“…Denninger et al showed that reduced MAPK9 levels exacerbated the clinical symptoms of the inflammatory response [ 56 ]. In addition, Yang et al observed exacerbation of lung inflammation and injury during sepsis and acute lung injury in mice with low MAPK9 levels [ 57 ]. Interestingly, miR-1275 is the subject of many studies.…”

Expression profile of mRNAs and miRNAs related to mitogen-activated kinases in HaCaT cell culture treated with lipopolysaccharide a and adalimumab

“…Also, Bertlesen et al confirmed that assessing changes in MAPK9 expression profile can be a useful marker for monitoring anti-IL17 therapy in patients with psoriasis [ 90 ]. Moreover, Yang et al observed an intensification of lung inflammation and injury in mice with low MAPK9 levels during sepsis and acute lung injury [ 91 ]. Interestingly, miR-1275 has been the focus of numerous studies, indicating its involvement in the regulation of various signaling pathways, such as MAPK, ERK/JNK, Wnt, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT).…”