title: Activation of Adenosine 2A receptor inhibits neutrophil apoptosis in an autophagy-dependent manner in mice with systemic inflammatory response syndrome.
abstract: Systemic inflammatory response syndrome (SIRS) is an overwhelming whole body inflammation caused by infectious diseases or sterile insults. Neutrophils are the dominant participants during inflammation, and their survival and death determine the initiation as well as resolution of SIRS. Apoptosis and autophagy are two fundamental cellular processes that modulating cell fate, but their correlation and regulators in neutrophils under SIRS condition have not been elucidated. In this study, we demonstrated that high dose of LPS induced both apoptosis and autophagy of neutrophils in a mouse SIRS model and LPS-stimulated neutrophils in vitro. Moreover, we found that the adenosine 2A receptor (A2AR), a known anti-inflammatory G protein-coupled receptor (GPCR), could inhibit LPS-induced neutrophil apoptosis by suppressing the LPS-induced autophagy. Activation of A2AR suppressed LPS-induced autophagy by inhibiting the ROS-JNK pathway as well as promoting GPCR βϒ subunit-AKT signaling. The A2AR-inhibited autophagy suppressed apoptosis of neutrophils by blocking caspase8, caspase3 and PARP signaling. These findings not only increase our understandings of neutrophils' fate and function in response to systemic inflammation, but also identify a novel anti-inflammatory role of A2AR in modulating neutrophils' survival during inflammation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, PRC.
authors.forename: Yang-Wuyue
authors.initials: YW
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, PRC.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, PRC.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, PRC.
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Ni
authors.affiliation: Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing 400042, PRC.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, PRC.
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, PRC.
authors.forename: Shuang-Shuang
authors.initials: SS
authors.lastname: Dai
mesh_terms: D036002:ADP Ribose Transferases; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001343:Autophagy / Q000276:immunology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology* / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D043705:Receptor, Adenosine A2A; D036002:ADP Ribose Transferases; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8