{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["He Y"],"funding":["Intramural NIH HHS","National Natural Science Foundation of China","Intramural program of NIAAA, NIH"],"pagination":["220-234"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5481471"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["66(1)"],"pubmed_abstract":["Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide, in which mitochondrial DNA (mtDNA) released by damaged hepatocytes activates neutrophils through binding of Toll-like receptor 9 (TLR9), further aggravating liver injury. Here, we demonstrated that mtDNA/TLR9 also activates a negative feedback pathway through induction of microRNA-223 (miR-223) to limit neutrophil overactivation and liver injury. After injection of APAP in mice, levels of miR-223, the most abundant miRNAs in neutrophils, were highly elevated in neutrophils. Disruption of the miR-223 gene exacerbated APAP-induced hepatic neutrophil infiltration, oxidative stress, and injury and enhanced TLR9 ligand-mediated activation of proinflammatory mediators in neutrophils. An additional deletion of the intercellular adhesion molecule 1 (ICAM-1) gene ameliorated APAP-induced neutrophil infiltration and liver injury in miR-223 knockout mice. In vitro experiments revealed that miR-223-deficient neutrophils were more susceptible to TLR9 agonist-mediated induction of proinflammatory mediators and nuclear factor kappa B (NF-κB) signaling, whereas overexpression of miR-223 attenuated these effects in neutrophils. Moreover, inhibition of TLR9 signaling by either treatment with a TLR9 inhibitor or by disruption of TLR9 gene partially, but significantly, suppressed miR-223 expression in neutrophils post-APAP injection. In contrast, activation of TLR9 up-regulated miR-223 expression in neutrophils in vivo and in vitro. Mechanistically, activation of TLR9 up-regulated miR-223 by enhancing NF-κB binding on miR-223 promoter, whereas miR-223 attenuated TLR9/NF-κB-mediated inflammation by targeting IκB kinase α expression. Collectively, up-regulation of miR-223 plays a key role in terminating the acute neutrophilic response and is a therapeutic target for treatment of APAP-induced liver failure. (Hepatology 2017;66:220-234)."],"journal":["Hepatology (Baltimore, Md.)"],"pubmed_title":["Hepatic mitochondrial DNA/Toll-like receptor 9/MicroRNA-223 forms a negative feedback loop to limit neutrophil overactivation and acetaminophen hepatotoxicity in mice."],"pmcid":["PMC5481471"],"funding_grant_id":["81273526","Z01 AA000368-07","81473268"],"pubmed_authors":["Gao B","Li J","Cao H","Feng D","Wang H","Ju C","Li M","Yang Y","He Y","Ramirez T","Gao Y","Cai Y","Kim SJ"],"additional_accession":[]},"is_claimable":false,"name":"Hepatic mitochondrial DNA/Toll-like receptor 9/MicroRNA-223 forms a negative feedback loop to limit neutrophil overactivation and acetaminophen hepatotoxicity in mice.","description":"Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide, in which mitochondrial DNA (mtDNA) released by damaged hepatocytes activates neutrophils through binding of Toll-like receptor 9 (TLR9), further aggravating liver injury. Here, we demonstrated that mtDNA/TLR9 also activates a negative feedback pathway through induction of microRNA-223 (miR-223) to limit neutrophil overactivation and liver injury. After injection of APAP in mice, levels of miR-223, the most abundant miRNAs in neutrophils, were highly elevated in neutrophils. Disruption of the miR-223 gene exacerbated APAP-induced hepatic neutrophil infiltration, oxidative stress, and injury and enhanced TLR9 ligand-mediated activation of proinflammatory mediators in neutrophils. An additional deletion of the intercellular adhesion molecule 1 (ICAM-1) gene ameliorated APAP-induced neutrophil infiltration and liver injury in miR-223 knockout mice. In vitro experiments revealed that miR-223-deficient neutrophils were more susceptible to TLR9 agonist-mediated induction of proinflammatory mediators and nuclear factor kappa B (NF-κB) signaling, whereas overexpression of miR-223 attenuated these effects in neutrophils. Moreover, inhibition of TLR9 signaling by either treatment with a TLR9 inhibitor or by disruption of TLR9 gene partially, but significantly, suppressed miR-223 expression in neutrophils post-APAP injection. In contrast, activation of TLR9 up-regulated miR-223 expression in neutrophils in vivo and in vitro. Mechanistically, activation of TLR9 up-regulated miR-223 by enhancing NF-κB binding on miR-223 promoter, whereas miR-223 attenuated TLR9/NF-κB-mediated inflammation by targeting IκB kinase α expression. Collectively, up-regulation of miR-223 plays a key role in terminating the acute neutrophilic response and is a therapeutic target for treatment of APAP-induced liver failure. (Hepatology 2017;66:220-234).","dates":{"release":"2017-01-01T00:00:00Z","publication":"2017 Jul","modification":"2024-11-09T08:04:54.305Z","creation":"2019-03-26T23:43:05Z"},"accession":"S-EPMC5481471","cross_references":{"pubmed":["28295449"],"doi":["10.1002/hep.29153"]}}