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

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...

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Autores principales:	Jing Yang, Hanh Chi Do-Umehara, Qiao Zhang, Huashan Wang, Changchun Hou, Huali Dong, Edith A. Perez, Marc A. Sala, Kishore R. Anekalla, James M. Walter, Shuwen Liu, Richard G. Wunderink, G.R. Scott Budinger, Jing Liu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	JNK2 sepsis lung inflammation and injury micro RNA (miRNA) smARF ubiquitination and degradation Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/c8ed6666624b4fa99b7c46a6cb604a90
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spelling	oai:doaj.org-article:c8ed6666624b4fa99b7c46a6cb604a902021-12-01T01:38:52ZmiR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury1664-322410.3389/fimmu.2021.700933https://doaj.org/article/c8ed6666624b4fa99b7c46a6cb604a902021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.700933/fullhttps://doaj.org/toc/1664-3224Sepsis 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.Jing YangHanh Chi Do-UmeharaQiao ZhangHuashan WangChangchun HouHuali DongEdith A. PerezMarc A. SalaKishore R. AnekallaJames M. WalterShuwen LiuShuwen LiuRichard G. WunderinkRichard G. WunderinkG.R. Scott BudingerJing LiuFrontiers Media S.A.articleJNK2sepsislung inflammation and injurymicro RNA (miRNA)smARFubiquitination and degradationImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	JNK2 sepsis lung inflammation and injury micro RNA (miRNA) smARF ubiquitination and degradation Immunologic diseases. Allergy RC581-607
spellingShingle	JNK2 sepsis lung inflammation and injury micro RNA (miRNA) smARF ubiquitination and degradation Immunologic diseases. Allergy RC581-607 Jing Yang Hanh Chi Do-Umehara Qiao Zhang Huashan Wang Changchun Hou Huali Dong Edith A. Perez Marc A. Sala Kishore R. Anekalla James M. Walter Shuwen Liu Shuwen Liu Richard G. Wunderink Richard G. Wunderink G.R. Scott Budinger Jing Liu miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury
description	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.
format	article
author	Jing Yang Hanh Chi Do-Umehara Qiao Zhang Huashan Wang Changchun Hou Huali Dong Edith A. Perez Marc A. Sala Kishore R. Anekalla James M. Walter Shuwen Liu Shuwen Liu Richard G. Wunderink Richard G. Wunderink G.R. Scott Budinger Jing Liu
author_facet	Jing Yang Hanh Chi Do-Umehara Qiao Zhang Huashan Wang Changchun Hou Huali Dong Edith A. Perez Marc A. Sala Kishore R. Anekalla James M. Walter Shuwen Liu Shuwen Liu Richard G. Wunderink Richard G. Wunderink G.R. Scott Budinger Jing Liu
author_sort	Jing Yang
title	miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury
title_short	miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury
title_full	miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury
title_fullStr	miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury
title_full_unstemmed	miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury
title_sort	mir-221-5p-mediated downregulation of jnk2 aggravates acute lung injury
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/c8ed6666624b4fa99b7c46a6cb604a90
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miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury

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