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 language | English |
---|---|
Pages (from-to) | 1971-1981 |
Number of pages | 11 |
Journal | Journal of Cerebral Blood Flow and Metabolism |
Volume | 37 |
Issue number | 6 |
DOIs | |
State | Published - 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