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Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Cardiac arrest\/cardiopulmonary resuscitation (CA\/CPR) represents one of the devastating medical emergencies and is associated with high mortality and neuro-disability. Post-cardiac arrest syndrome (PCAS) is mechanistically ascribed to acute systemic ischemia\/reperfusion(I\/R) injury. The lncRNA\/microRNA\/mRNA networks have been found to play crucial roles in the pathogenesis of the hypoxia-responsive diseases. Nonetheless, the precise molecular mechanisms by which lncRNA\/miRNA\/mRNA axes are involved in the astrocyte\u2013microglia crosstalk in CA\/CPR have not been fully elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We collected and purified the exosomes from the blood of CA\/CPR patients and supernatant of OGD\/R-stimulated astrocytes. On the basis of microarray analysis, bioinformatic study, and luciferase activity determination, we speculated that lncRNA GAS5\/miR-137 is implicated in the astrocyte\u2013microglia crosstalk under the insult of systemic I\/R injury. The regulation of lncRNA GAS5\/miR-137 on INPP4B was examined by cellular transfection in OGD\/R cell culture and by lateral ventricle injection with miR-137 agomir in CA\/CPR mice model. Flow cytometry and immunofluorescence staining were performed to detect the microglial apoptosis, M1\/M2 phenotype transformation, and neuroinflammation. Neurological scoring and behavior tests were conducted in CA\/CPR group, with miR-137 agomir lateral-ventricle infusion and in their controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In all the micRNAs, miR-137 was among the top 10 micRNAs that experienced greatest changes, in both the blood of CA\/CPR patients and supernatant of OGD\/R-stimulated astrocytes. Bioinformatic analysis revealed that miR-137 was sponged by lncRNA GAS5, targeting INPP4B, and the result was confirmed by Luciferase activity assay. qRT-PCR and Western blotting showed that lncRNA GAS5 and INPP4B were over-expressed whereas miR-137 was downregulated in the blood of CA\/CPR patients, OGD\/R-stimulated astrocytes, and brain tissue of CA\/CPR mice. Silencing lncRNA GAS5 suppressed INPP4B expression, but over-expression of miR-137 negatively modulated its expression. Western blotting exhibited that PI3K and Akt phosphorylation was increased when lncRNA GAS5 was silenced or miR-137 was over-expressed. However, PI3K and Akt phosphorylation was notably suppressed in the absence of miR-137, almost reversing their phosphorylation in the silencing lncRNA GAS5 group. Then we found that GAS5 siRNA or miR-137 mimic significantly increased cell viability and alleviated apoptosis after OGD\/R injury. Furthermore, over-expression of miR-137 attenuated microglial apoptosis and neuroinflammation in CA\/CPR mice model, exhibiting significantly better behavioral tests after CA\/CPR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>LncRNA GAS5\/miR-137 may be involved in the astrocyte\u2013microglia communication that inhibits PI3K\/Akt signaling activation <jats:italic>via<\/jats:italic> regulation of INPP4B during CA\/CPR.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.790750","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T04:54:16Z","timestamp":1641876856000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["LncRNA GAS5\/miR-137 Is a Hypoxia-Responsive Axis Involved in Cardiac Arrest and Cardiopulmonary Cerebral Resuscitation"],"prefix":"10.3389","volume":"12","author":[{"given":"Wang","family":"Jing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xie","family":"Tuxiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Xiaobing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Guijun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Lulu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Jie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhan","family":"Liying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiong","family":"Xiaoxing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyu","family":"Jingjun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(18)30315-5","article-title":"Out-Of-Hospital Cardiac Arrest: in-Hospital Intervention Strategies","volume":"391","author":"Hassager","year":"2018","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678x19835552","article-title":"The Post-Cardiac Arrest Syndrome: A Case for Lung-Brain Coupling and Opportunities for Neuroprotection","volume":"39","author":"Mai","year":"2019","journal-title":"J Cereb Blood Flow Metab"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000023891.80661.ad","article-title":"Successful Cardiopulmonary Resuscitation After Cardiac Arrest as a \"Sepsis-Like\" Syndrome","volume":"106","author":"Adrie","year":"2002","journal-title":"Circulation"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.1696","article-title":"In-Hospital Cardiac Arrest: A Review","volume":"321","author":"Andersen","year":"2019","journal-title":"Jama"},{"key":"B5","doi-asserted-by":"publisher","first-page":"R147","DOI":"10.1186\/cc12826","article-title":"Factors Predicting the Use of Therapeutic Hypothermia and Survival in Unconscious Out-of-Hospital Cardiac Arrest Patients Admitted to the ICU","volume":"17","author":"Lindner","year":"2013","journal-title":"Crit Care"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-021-06548-2","article-title":"Sekhon MJIcm. 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