miRNA-200c-3p is crucial in acute respiratory distress syndrome
Citation: Cell Discovery
miRNA-200c-3p is crucial in acute respiratory distress syndrome
Qiang Liu 0
Jianchao Du 0
Xuezhong Yu 1
Jun Xu 1
Fengming Huang 0
Xiaoyun Li 0
Cong Zhang 2
Xiao Li 3
Jiahui Chang 0
Daozhen Shang 0
Yan Zhao 0
Mingyao Tian 3
Huijun Lu 3
Jiantao Xu 0
Chang Li 3
Huadong Zhu 1
Ningyi Jin 3
Chengyu Jiang 0 4
0 Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College , Beijing , China
1 Department of Emergency, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences , Beijing , China
2 School of Life Science, University of Science and Technology of China , Hefei , China
3 Genetic Engineering Laboratory, Institute of Military Veterinary, Academy of Military Medical Sciences , Changchun , China
4 State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , China
Influenza infection and pneumonia are known to cause much of their mortality by inducing acute respiratory distress syndrome (ARDS), which is the most severe form of acute lung injury (ALI). Angiotensin-converting enzyme 2 (ACE2), which is a negative regulator of angiotensin II in the renin-angiotensin system, has been reported to have a crucial role in ALI. Downregulation of ACE2 is always associated with the ALI or ARDS induced by avian influenza virus, severe acute respiratory syndrome-coronavirus, respiratory syncytial virus and sepsis. However, the molecular mechanism of the decreased expression of ACE2 in ALI is unclear. Here we show that avian influenza virus H5N1 induced the upregulation of miR-200c-3p, which was then demonstrated to target the 3?-untranslated region of ACE2. Then, we found that nonstructural protein 1 and viral RNA of H5N1 contributed to the induction of miR-200c-3p during viral infection. Additionally, the synthetic analog of viral double-stranded RNA (poly (I:C)), bacterial lipopolysaccharide and lipoteichoic acid can all markedly increase the expression of miR-200c-3p in a nuclear factor-?B-dependent manner. Furthermore, markedly elevated plasma levels of miR-200c-3p were observed in severe pneumonia patients. The inhibition of miR-200c-3p ameliorated the ALI induced by H5N1 virus infection in vivo, indicating a potential therapeutic target. Therefore, we identify a shared mechanism of viral and bacterial lung infection-induced ALI/ARDS via nuclear factor-?B-dependent upregulation of miR-200c-3p to reduce ACE2 levels, which leads increased angiotensin II levels and subsequently causes lung injury.
Introduction
Acute respiratory distress syndrome (ARDS), the
most severe form of acute lung injury (ALI), is the
main predisposing factor in highly pathogenic avian
influenza virus-induced death cases [
1, 2
]. The ALI
caused by influenza infection can facilitate bacterial
superinfection, which is a major factor that promotes
mortality and disease severity [3]. From 2003 to 2016,
highly pathogenic avian H5N1 influenza virus
has caused 856 human infection cases worldwide with a
high mortality rate of 52.8% (http://101.96.8.164/www.
who.int/entity/influenza/human_animal_interface/2017_
01_16_tableH5N1.pdf). Currently, China is undergoing
its fifth epidemic of human infections of avian H7N9
influenza virus. Until 16 January 2017, 918
H7N9infected human cases with at least 359 deaths have
been reported to World Health Organization (http://101.
96.8.165/www.who.int/influenza/human_animal_inter
face/Influenza_Summary_IRA_HA_interface_01_16_
2017_FINAL.pdf?ua = 1). With high mutation and
reassortment rates, influenza viruses have evolved with a
rapid resistance to the current vaccines and anti-viral
drugs, making an avian influenza pandemic an urgent
unresolved threat to human health [
4?6
].
Angiotensin-converting enzyme 2 (ACE2) was
firstly identified from human cardiac left ventricle
complementary DNA (cDNA) library and lymphoma
cDNA library by two separate groups [
7, 8
]. ACE2
inactivates angiotensin II (Ang II) by cleaving it to
produce Ang 1?7 [9]. Ang II binds to the Ang II type 1
and type 2 receptors with strong affinity, mediating
regulation of blood pressure, body fluid balance,
inflammation, cell proliferation, hypertrophy and
fibrosis [
10?12
]. Reduced expression levels of ACE2
have been reported in hypertension and chronic kidney
disease [
13, 14
]. In addition, ACE2 was identified as a
key regulator of dietary amino-acid homeostasis
and gut microbial ecology [15]. We previously
demonstrated that ACE2 counteracts the development
of severe ALI or ARDS induced by avian influenza
virus, severe acute respiratory syndrome-coronavirus
spikes, sepsis and acid aspiration in mice [
16?18
].
Administration of recombinant ACE2 or the Ang II
receptor blocker losartan can ameliorate H5N1
virus infection-induced ALI [
16, 19
]. Moreover, ACE2
was also reported to have a protective ro (...truncated)