Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1.
Identifieur interne : 000084 ( PubMed/Corpus ); précédent : 000083; suivant : 000085Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1.
Auteurs : Yan Li ; Dongmei Zhou ; Yinghui Ren ; Zimu Zhang ; Xiangdong Guo ; Mingkun Ma ; Zhenyi Xue ; Jienv Lv ; Hongkun Liu ; Qing Xi ; Long Jia ; Lijuan Zhang ; Ying Liu ; Qi Zhang ; Jun Yan ; Yurong Da ; Fei Gao ; Jianbo Yue ; Zhi Yao ; Rongxin ZhangSource :
- Autophagy [ 1554-8635 ] ; 2019.
Abstract
Microglia are innate immune cells in the central nervous system (CNS), that supplies neurons with key factors for executing autophagosomal/lysosomal functions. Macroautophagy/autophagy is a cellular catabolic process that maintains cell balance in response to stress-related stimulation. Abnormal autophagy occurs with many pathologies, such as cancer, and autoimmune and neurodegenerative diseases. Hence, clarification of the mechanisms of autophagy regulation is of utmost importance. Recently, researchers presented microRNAs (miRNAs) as novel and potent modulators of autophagic activity. Here, we found that Mir223 deficiency significantly ameliorated CNS inflammation, demyelination and the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) and increased resting microglia and autophagy in brain microglial cells. In contrast, the autophagy inhibitor 3-methylademine (3-MA) aggravated the clinical symptoms of EAE in wild-type (WT) and Mir223-deficienct mice. Furthermore, it was confirmed that Mir223 deficiency in mice increased the protein expression of ATG16L1 (autophagy related 16-like 1 [S. cerevisiae]) and LC3-II in bone marrow-derived macrophage cells compared with cells from WT mice. Indeed, the cellular level of Atg16l1 was decreased in BV2 cells upon Mir223 overexpression and increased following the introduction of antagomirs. We also showed that the 3' UTR of Atg16l1 contained functional Mir223-responsive sequences and that overexpression of ATG16L1 returned autophagy to normal levels even in the presence of Mir223 mimics. Collectively, these data indicate that Mir223 is a novel and important regulator of autophagy and that Atg16l1 is a Mir223 target in this process, which may have implications for improving our understanding of the neuroinflammatory process of EAE. Abbreviations: 3-MA: 3-methylademine; ACTB/β-actin: actin, beta; ATG: autophagy related; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CNR2: cannabinoid receptor 2 (macrophage); CNS: central nervous system; CQ: chloroquine; EAE: experimental autoimmune encephalomyelitis; FOXO3: forkhead box O3; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; H&E: hematoxylin and eosin; ITGAM: integrin alpha M; LPS: lipoplysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; miRNAs: microRNAs; MS: multiple sclerosis; PPARG: peroxisome proliferator activated receptor gamma; PTPRC: protein tyrosine phosphatase, receptor type, C; RA: rheumatoid arthritis; SQSTM1: sequestosome 1; TB: tuberculosis; TIMM23: translocase of inner mitochondrial membrane 23; TLR: toll-like receptor.
DOI: 10.1080/15548627.2018.1522467
PubMed: 30208760
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1.</title><author><name sortKey="Li, Yan" sort="Li, Yan" uniqKey="Li Y" first="Yan" last="Li">Yan Li</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhou, Dongmei" sort="Zhou, Dongmei" uniqKey="Zhou D" first="Dongmei" last="Zhou">Dongmei Zhou</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Ren, Yinghui" sort="Ren, Yinghui" uniqKey="Ren Y" first="Yinghui" last="Ren">Yinghui Ren</name><affiliation><nlm:affiliation>b Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute , Tianjin Medical University General Hospital , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Zimu" sort="Zhang, Zimu" uniqKey="Zhang Z" first="Zimu" last="Zhang">Zimu Zhang</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Guo, Xiangdong" sort="Guo, Xiangdong" uniqKey="Guo X" first="Xiangdong" last="Guo">Xiangdong Guo</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Ma, Mingkun" sort="Ma, Mingkun" uniqKey="Ma M" first="Mingkun" last="Ma">Mingkun Ma</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Xue, Zhenyi" sort="Xue, Zhenyi" uniqKey="Xue Z" first="Zhenyi" last="Xue">Zhenyi Xue</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Lv, Jienv" sort="Lv, Jienv" uniqKey="Lv J" first="Jienv" last="Lv">Jienv Lv</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Hongkun" sort="Liu, Hongkun" uniqKey="Liu H" first="Hongkun" last="Liu">Hongkun Liu</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Xi, Qing" sort="Xi, Qing" uniqKey="Xi Q" first="Qing" last="Xi">Qing Xi</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Jia, Long" sort="Jia, Long" uniqKey="Jia L" first="Long" last="Jia">Long Jia</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Lijuan" sort="Zhang, Lijuan" uniqKey="Zhang L" first="Lijuan" last="Zhang">Lijuan Zhang</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Ying" sort="Liu, Ying" uniqKey="Liu Y" first="Ying" last="Liu">Ying Liu</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Qi" sort="Zhang, Qi" uniqKey="Zhang Q" first="Qi" last="Zhang">Qi Zhang</name><affiliation><nlm:affiliation>e Institute of Integrative Medicines for Acute Abdominal Diseases , Nankai Hospital , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Yan, Jun" sort="Yan, Jun" uniqKey="Yan J" first="Jun" last="Yan">Jun Yan</name><affiliation><nlm:affiliation>f Tianjin Institute of Animal husbandry and veterinary , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Da, Yurong" sort="Da, Yurong" uniqKey="Da Y" first="Yurong" last="Da">Yurong Da</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Gao, Fei" sort="Gao, Fei" uniqKey="Gao F" first="Fei" last="Gao">Fei Gao</name><affiliation><nlm:affiliation>g State Key Laboratory of Reproductive Biology, Institute of Zoology , Chinese Academy of Sciences , Beijing , China.</nlm:affiliation></affiliation></author><author><name sortKey="Yue, Jianbo" sort="Yue, Jianbo" uniqKey="Yue J" first="Jianbo" last="Yue">Jianbo Yue</name><affiliation><nlm:affiliation>h Department of Biomedical Sciences , City University of Hong Kong , Hong Kong , China.</nlm:affiliation></affiliation></author><author><name sortKey="Yao, Zhi" sort="Yao, Zhi" uniqKey="Yao Z" first="Zhi" last="Yao">Zhi Yao</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Rongxin" sort="Zhang, Rongxin" uniqKey="Zhang R" first="Rongxin" last="Zhang">Rongxin Zhang</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:30208760</idno><idno type="pmid">30208760</idno><idno type="doi">10.1080/15548627.2018.1522467</idno><idno type="wicri:Area/PubMed/Corpus">000084</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000084</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1.</title><author><name sortKey="Li, Yan" sort="Li, Yan" uniqKey="Li Y" first="Yan" last="Li">Yan Li</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhou, Dongmei" sort="Zhou, Dongmei" uniqKey="Zhou D" first="Dongmei" last="Zhou">Dongmei Zhou</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Ren, Yinghui" sort="Ren, Yinghui" uniqKey="Ren Y" first="Yinghui" last="Ren">Yinghui Ren</name><affiliation><nlm:affiliation>b Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute , Tianjin Medical University General Hospital , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Zimu" sort="Zhang, Zimu" uniqKey="Zhang Z" first="Zimu" last="Zhang">Zimu Zhang</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Guo, Xiangdong" sort="Guo, Xiangdong" uniqKey="Guo X" first="Xiangdong" last="Guo">Xiangdong Guo</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Ma, Mingkun" sort="Ma, Mingkun" uniqKey="Ma M" first="Mingkun" last="Ma">Mingkun Ma</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Xue, Zhenyi" sort="Xue, Zhenyi" uniqKey="Xue Z" first="Zhenyi" last="Xue">Zhenyi Xue</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Lv, Jienv" sort="Lv, Jienv" uniqKey="Lv J" first="Jienv" last="Lv">Jienv Lv</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Hongkun" sort="Liu, Hongkun" uniqKey="Liu H" first="Hongkun" last="Liu">Hongkun Liu</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Xi, Qing" sort="Xi, Qing" uniqKey="Xi Q" first="Qing" last="Xi">Qing Xi</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Jia, Long" sort="Jia, Long" uniqKey="Jia L" first="Long" last="Jia">Long Jia</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Lijuan" sort="Zhang, Lijuan" uniqKey="Zhang L" first="Lijuan" last="Zhang">Lijuan Zhang</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Ying" sort="Liu, Ying" uniqKey="Liu Y" first="Ying" last="Liu">Ying Liu</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Qi" sort="Zhang, Qi" uniqKey="Zhang Q" first="Qi" last="Zhang">Qi Zhang</name><affiliation><nlm:affiliation>e Institute of Integrative Medicines for Acute Abdominal Diseases , Nankai Hospital , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Yan, Jun" sort="Yan, Jun" uniqKey="Yan J" first="Jun" last="Yan">Jun Yan</name><affiliation><nlm:affiliation>f Tianjin Institute of Animal husbandry and veterinary , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Da, Yurong" sort="Da, Yurong" uniqKey="Da Y" first="Yurong" last="Da">Yurong Da</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Gao, Fei" sort="Gao, Fei" uniqKey="Gao F" first="Fei" last="Gao">Fei Gao</name><affiliation><nlm:affiliation>g State Key Laboratory of Reproductive Biology, Institute of Zoology , Chinese Academy of Sciences , Beijing , China.</nlm:affiliation></affiliation></author><author><name sortKey="Yue, Jianbo" sort="Yue, Jianbo" uniqKey="Yue J" first="Jianbo" last="Yue">Jianbo Yue</name><affiliation><nlm:affiliation>h Department of Biomedical Sciences , City University of Hong Kong , Hong Kong , China.</nlm:affiliation></affiliation></author><author><name sortKey="Yao, Zhi" sort="Yao, Zhi" uniqKey="Yao Z" first="Zhi" last="Yao">Zhi Yao</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Rongxin" sort="Zhang, Rongxin" uniqKey="Zhang R" first="Rongxin" last="Zhang">Rongxin Zhang</name><affiliation><nlm:affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Autophagy</title><idno type="eISSN">1554-8635</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Microglia are innate immune cells in the central nervous system (CNS), that supplies neurons with key factors for executing autophagosomal/lysosomal functions. Macroautophagy/autophagy is a cellular catabolic process that maintains cell balance in response to stress-related stimulation. Abnormal autophagy occurs with many pathologies, such as cancer, and autoimmune and neurodegenerative diseases. Hence, clarification of the mechanisms of autophagy regulation is of utmost importance. Recently, researchers presented microRNAs (miRNAs) as novel and potent modulators of autophagic activity. Here, we found that Mir223 deficiency significantly ameliorated CNS inflammation, demyelination and the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) and increased resting microglia and autophagy in brain microglial cells. In contrast, the autophagy inhibitor 3-methylademine (3-MA) aggravated the clinical symptoms of EAE in wild-type (WT) and Mir223-deficienct mice. Furthermore, it was confirmed that Mir223 deficiency in mice increased the protein expression of ATG16L1 (autophagy related 16-like 1 [S. cerevisiae]) and LC3-II in bone marrow-derived macrophage cells compared with cells from WT mice. Indeed, the cellular level of Atg16l1 was decreased in BV2 cells upon Mir223 overexpression and increased following the introduction of antagomirs. We also showed that the 3' UTR of Atg16l1 contained functional Mir223-responsive sequences and that overexpression of ATG16L1 returned autophagy to normal levels even in the presence of Mir223 mimics. Collectively, these data indicate that Mir223 is a novel and important regulator of autophagy and that Atg16l1 is a Mir223 target in this process, which may have implications for improving our understanding of the neuroinflammatory process of EAE. Abbreviations: 3-MA: 3-methylademine; ACTB/β-actin: actin, beta; ATG: autophagy related; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CNR2: cannabinoid receptor 2 (macrophage); CNS: central nervous system; CQ: chloroquine; EAE: experimental autoimmune encephalomyelitis; FOXO3: forkhead box O3; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; H&E: hematoxylin and eosin; ITGAM: integrin alpha M; LPS: lipoplysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; miRNAs: microRNAs; MS: multiple sclerosis; PPARG: peroxisome proliferator activated receptor gamma; PTPRC: protein tyrosine phosphatase, receptor type, C; RA: rheumatoid arthritis; SQSTM1: sequestosome 1; TB: tuberculosis; TIMM23: translocase of inner mitochondrial membrane 23; TLR: toll-like receptor.</div></front></TEI><pubmed><MedlineCitation Status="In-Process" Owner="NLM"><PMID Version="1">30208760</PMID><DateRevised><Year>2020</Year><Month>03</Month><Day>10</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1554-8635</ISSN><JournalIssue CitedMedium="Internet"><Volume>15</Volume><Issue>3</Issue><PubDate><Year>2019</Year><Month>03</Month></PubDate></JournalIssue><Title>Autophagy</Title><ISOAbbreviation>Autophagy</ISOAbbreviation></Journal><ArticleTitle>Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1.</ArticleTitle><Pagination><MedlinePgn>478-492</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1080/15548627.2018.1522467</ELocationID><Abstract><AbstractText>Microglia are innate immune cells in the central nervous system (CNS), that supplies neurons with key factors for executing autophagosomal/lysosomal functions. Macroautophagy/autophagy is a cellular catabolic process that maintains cell balance in response to stress-related stimulation. Abnormal autophagy occurs with many pathologies, such as cancer, and autoimmune and neurodegenerative diseases. Hence, clarification of the mechanisms of autophagy regulation is of utmost importance. Recently, researchers presented microRNAs (miRNAs) as novel and potent modulators of autophagic activity. Here, we found that Mir223 deficiency significantly ameliorated CNS inflammation, demyelination and the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) and increased resting microglia and autophagy in brain microglial cells. In contrast, the autophagy inhibitor 3-methylademine (3-MA) aggravated the clinical symptoms of EAE in wild-type (WT) and Mir223-deficienct mice. Furthermore, it was confirmed that Mir223 deficiency in mice increased the protein expression of ATG16L1 (autophagy related 16-like 1 [S. cerevisiae]) and LC3-II in bone marrow-derived macrophage cells compared with cells from WT mice. Indeed, the cellular level of Atg16l1 was decreased in BV2 cells upon Mir223 overexpression and increased following the introduction of antagomirs. We also showed that the 3' UTR of Atg16l1 contained functional Mir223-responsive sequences and that overexpression of ATG16L1 returned autophagy to normal levels even in the presence of Mir223 mimics. Collectively, these data indicate that Mir223 is a novel and important regulator of autophagy and that Atg16l1 is a Mir223 target in this process, which may have implications for improving our understanding of the neuroinflammatory process of EAE. Abbreviations: 3-MA: 3-methylademine; ACTB/β-actin: actin, beta; ATG: autophagy related; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CNR2: cannabinoid receptor 2 (macrophage); CNS: central nervous system; CQ: chloroquine; EAE: experimental autoimmune encephalomyelitis; FOXO3: forkhead box O3; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; H&E: hematoxylin and eosin; ITGAM: integrin alpha M; LPS: lipoplysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; miRNAs: microRNAs; MS: multiple sclerosis; PPARG: peroxisome proliferator activated receptor gamma; PTPRC: protein tyrosine phosphatase, receptor type, C; RA: rheumatoid arthritis; SQSTM1: sequestosome 1; TB: tuberculosis; TIMM23: translocase of inner mitochondrial membrane 23; TLR: toll-like receptor.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Yan</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhou</LastName><ForeName>Dongmei</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ren</LastName><ForeName>Yinghui</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>b Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute , Tianjin Medical University General Hospital , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Zimu</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Guo</LastName><ForeName>Xiangdong</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ma</LastName><ForeName>MingKun</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>c Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xue</LastName><ForeName>Zhenyi</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lv</LastName><ForeName>Jienv</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>d Hexi Women & Children Healthcare and Family Planning Service Center , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Hongkun</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xi</LastName><ForeName>Qing</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jia</LastName><ForeName>Long</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Lijuan</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Ying</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Qi</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>e Institute of Integrative Medicines for Acute Abdominal Diseases , Nankai Hospital , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yan</LastName><ForeName>Jun</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>f Tianjin Institute of Animal husbandry and veterinary , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Da</LastName><ForeName>Yurong</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gao</LastName><ForeName>Fei</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>g State Key Laboratory of Reproductive Biology, Institute of Zoology , Chinese Academy of Sciences , Beijing , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yue</LastName><ForeName>Jianbo</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>h Department of Biomedical Sciences , City University of Hong Kong , Hong Kong , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yao</LastName><ForeName>Zhi</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Rongxin</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>i Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics , Guangdong Pharmaceutical University , Guangzhou , China.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2018</Year><Month>09</Month><Day>22</Day></ArticleDate></Article><MedlineJournalInfo><Country>United 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