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- Publisher Website: 10.1164/rccm.201604-0730OC
- Scopus: eid_2-s2.0-85011816347
- PMID: 27735193
- WOS: WOS:000398017200012
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Article: DJ-1/PARK7 Impairs bacterial clearance in sepsis
Title | DJ-1/PARK7 Impairs bacterial clearance in sepsis |
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Authors | Amatullah, HajeraShan, YuexinBeauchamp, Brittany L.Gali, Patricia L.Gupta, SahilMaron-Gutierrez, TatianaSpeck, Edwin R.Fox-Robichaud, Alison E.Tsang, Jennifer L.Y.Mei, Shirley H.J.Mak, Tak W.Rocco, Patricia R.M.Semple, John W.Zhang, HaiboHu, PingzhaoMarshal, John C.Stewart, Duncan J.Harper, Mary EllenLiaw, Patricia C.Liles, W. ConradDos Santos, Claudia C. |
Keywords | DJ-1/PARK7 Reactive oxygen Species Bacterial Clearance NADPH oxidase Sepsis |
Issue Date | 2017 |
Citation | American Journal of Respiratory and Critical Care Medicine, 2017, v. 195, n. 7, p. 889-905 How to Cite? |
Abstract | © 2017 by the American Thoracic Society. Rationale: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. Objectives: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role ofDJ-1 in bacterial sepsis. Methods: We used cell and murine models with gain- A nd loss-offunction experiments, plasma, and cells from patients with sepsis. Measurements and Main Results: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bonemarrow-derivedmononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of theNADPHoxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking downDJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst.DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. Conclusions: These novel findings reveal DJ-1 impairs optimalROS production for bacterial killing with important implications for host survival in sepsis. |
Persistent Identifier | http://hdl.handle.net/10722/292997 |
ISSN | 2023 Impact Factor: 19.3 2023 SCImago Journal Rankings: 5.336 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Amatullah, Hajera | - |
dc.contributor.author | Shan, Yuexin | - |
dc.contributor.author | Beauchamp, Brittany L. | - |
dc.contributor.author | Gali, Patricia L. | - |
dc.contributor.author | Gupta, Sahil | - |
dc.contributor.author | Maron-Gutierrez, Tatiana | - |
dc.contributor.author | Speck, Edwin R. | - |
dc.contributor.author | Fox-Robichaud, Alison E. | - |
dc.contributor.author | Tsang, Jennifer L.Y. | - |
dc.contributor.author | Mei, Shirley H.J. | - |
dc.contributor.author | Mak, Tak W. | - |
dc.contributor.author | Rocco, Patricia R.M. | - |
dc.contributor.author | Semple, John W. | - |
dc.contributor.author | Zhang, Haibo | - |
dc.contributor.author | Hu, Pingzhao | - |
dc.contributor.author | Marshal, John C. | - |
dc.contributor.author | Stewart, Duncan J. | - |
dc.contributor.author | Harper, Mary Ellen | - |
dc.contributor.author | Liaw, Patricia C. | - |
dc.contributor.author | Liles, W. Conrad | - |
dc.contributor.author | Dos Santos, Claudia C. | - |
dc.date.accessioned | 2020-11-17T14:57:39Z | - |
dc.date.available | 2020-11-17T14:57:39Z | - |
dc.date.issued | 2017 | - |
dc.identifier.citation | American Journal of Respiratory and Critical Care Medicine, 2017, v. 195, n. 7, p. 889-905 | - |
dc.identifier.issn | 1073-449X | - |
dc.identifier.uri | http://hdl.handle.net/10722/292997 | - |
dc.description.abstract | © 2017 by the American Thoracic Society. Rationale: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. Objectives: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role ofDJ-1 in bacterial sepsis. Methods: We used cell and murine models with gain- A nd loss-offunction experiments, plasma, and cells from patients with sepsis. Measurements and Main Results: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bonemarrow-derivedmononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of theNADPHoxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking downDJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst.DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. Conclusions: These novel findings reveal DJ-1 impairs optimalROS production for bacterial killing with important implications for host survival in sepsis. | - |
dc.language | eng | - |
dc.relation.ispartof | American Journal of Respiratory and Critical Care Medicine | - |
dc.subject | DJ-1/PARK7 | - |
dc.subject | Reactive oxygen Species | - |
dc.subject | Bacterial Clearance | - |
dc.subject | NADPH oxidase | - |
dc.subject | Sepsis | - |
dc.title | DJ-1/PARK7 Impairs bacterial clearance in sepsis | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1164/rccm.201604-0730OC | - |
dc.identifier.pmid | 27735193 | - |
dc.identifier.scopus | eid_2-s2.0-85011816347 | - |
dc.identifier.volume | 195 | - |
dc.identifier.issue | 7 | - |
dc.identifier.spage | 889 | - |
dc.identifier.epage | 905 | - |
dc.identifier.eissn | 1535-4970 | - |
dc.identifier.isi | WOS:000398017200012 | - |
dc.identifier.issnl | 1073-449X | - |