Recombinant Gas6 augments Axl and facilitates immune restoration in an intracerebral hemorrhage mouse model

Lu Sha Tong, An Wen Shao, Yi Bo Ou, Zhen Ni Guo, Anatol Manaenko, Brandon J. Dixon, Jiping Tang, Min Lou, John H. Zhang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1971-1981
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume37
Issue number6
DOIs
StatePublished - Jun 1 2017

ASJC Scopus Subject Areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Keywords

  • Axl
  • Gas6
  • Intracerebral hemorrhage
  • Suppressor of cytokine signaling 1
  • Suppressor of cytokine signaling 3
  • Axl Receptor Tyrosine Kinase
  • Intercellular Signaling Peptides and Proteins/genetics
  • Male
  • Recombinant Proteins
  • Mice, Inbred Strains
  • Administration, Intranasal
  • Immunity, Innate/drug effects
  • Mice, Knockout
  • Triazoles/pharmacology
  • Animals
  • Behavior, Animal/drug effects
  • Receptor Protein-Tyrosine Kinases/agonists
  • Benzocycloheptenes/pharmacology
  • Cerebral Hemorrhage/drug therapy
  • Cytokines/metabolism
  • Proto-Oncogene Proteins/agonists
  • Disease Models, Animal

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