title: Recombinant Gas6 augments Axl and facilitates immune restoration in an intracerebral hemorrhage mouse model.
abstract: Axl, a tyrosine kinase receptor, was recently identified as an essential component regulating innate immune response. Suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 are potent Axl-inducible negative inflammatory regulators. This study investigated the role of Axl signaling pathway in immune restoration in an autologous blood-injection mouse model of intracerebral hemorrhage. Recombinant growth arrest-specific 6 (Gas6) and R428 were administrated as specific agonist and antagonist. In vivo knockdown of Axl or suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 by siRNA was applied. After intracerebral hemorrhage, the expression of endogenous Axl, soluble Axl, and Gas6 was increased, whereas the expression of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 was inhibited. Recombinant growth arrest-specific 6 administration alleviated brain edema and improved neurobehavioral performances. Moreover, enhanced Axl phosphorylation with cleavage of soluble Axl (sAxl), and an upregulation of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 were observed. In vivo knockdown of Axl and R428 administration both abolished the effect of recombinant growth arrest-specific 6 on brain edema and also decreased the expression suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3. In vivo knockdown of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 aggravated cytokine releasing despite of recombinant growth arrest-specific 6. In conclusion, Axl plays essential role in immune restoration after intracerebral hemorrhage. And recombinant growth arrest-specific 6 attenuated brain injury after intracerebral hemorrhage, probably by enhancing Axl phosphorylation and production of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3.
authors.affiliation: 1 Department of Anesthesiology, School of Medicine, Loma Linda University, CA, USA.|2 Department of Neurology, School of Medicine, the 2nd Affiliated Hospital of Zhejiang University, Hangzhou, China.
authors.forename: Lu-Sha
authors.initials: LS
authors.lastname: Tong
authors.affiliation: 1 Department of Anesthesiology, School of Medicine, Loma Linda University, CA, USA.|3 Department of Neurosurgery, School of Medicine, the 2nd Affiliated Hospital of Zhejiang University, Hangzhou, China.
authors.forename: An-Wen
authors.initials: AW
authors.lastname: Shao
authors.affiliation: 1 Department of Anesthesiology, School of Medicine, Loma Linda University, CA, USA.|4 Department of Neurosurgery, Tong-ji Hospital, Wuhan, China.
authors.forename: Yi-Bo
authors.initials: YB
authors.lastname: Ou
authors.affiliation: 1 Department of Anesthesiology, School of Medicine, Loma Linda University, CA, USA.|5 Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, China.
authors.forename: Zhen-Ni
authors.initials: ZN
authors.lastname: Guo
authors.affiliation: 1 Department of Anesthesiology, School of Medicine, Loma Linda University, CA, USA.
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.affiliation: 1 Department of Anesthesiology, School of Medicine, Loma Linda University, CA, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Dixon
authors.affiliation: 2 Department of Neurology, School of Medicine, the 2nd Affiliated Hospital of Zhejiang University, Hangzhou, China.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: 2 Department of Neurology, School of Medicine, the 2nd Affiliated Hospital of Zhejiang University, Hangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Lou
authors.affiliation: 1 Department of Anesthesiology, School of Medicine, Loma Linda University, CA, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001567:Benzocycloheptenes / Q000494:pharmacology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D011994:Recombinant Proteins; D014230:Triazoles / Q000494:pharmacology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001567:Benzocycloheptenes; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D014230:Triazoles; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C548378:bemcentinib; C000722290:AXL receptor tyrosine kinase, mouse
keywords: Axl; Gas6; intracerebral hemorrhage; suppressor of cytokine signaling 1; suppressor of cytokine signaling 3