Axl activation attenuates neuroinflammation by inhibiting the TLR/TRAF/NF-κB pathway after MCAO in rats

• Published in: Neurobiology of disease 2018-02, Vol.110, p.59-67
• Main Authors: Wu, Guangyong, McBride, Devin W., Zhang, John H.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Axl; Brain - drug effects; Brain - metabolism; Brain - pathology; Enzyme Activation - drug effects; Growth-arrest-specific protein 6; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Inflammation; Inflammation - metabolism; Inflammation - pathology; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Male; Middle cerebral artery occlusion; Neuroprotective Agents - pharmacology; NF-kappa B - metabolism; Rats; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases - metabolism; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; Toll-like receptor; Toll-Like Receptors - metabolism; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins - metabolism
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2017.11.009

Ischemic stroke activates Toll-like receptors (TLRs), triggering rapid inflammatory cytokine production. Axl signaling has multiple roles, including regulating cytokine secretion, clearing apoptotic cells, and maintaining cell survival, however, its role in inflammation after ischemic stroke has not been examined. We hypothesized that activation of Axl by recombinant Growth-arrest-specific protein 6 (rGas6) attenuates neuroinflammation by inhibiting the TLR/TRAF/NF-κB pathway after middle cerebral artery occlusion (MCAO) in rats. Sprague-Dawley rats were subjected to 2h of MCAO. One hour after reperfusion, the rats were given an intranasal injection of rGas6, vehicle, or R428 (Axl receptor inhibitor). Neurological scores, infarct volumes, immunofluorescence staining, Morris Water Maze, rotarod test and histology alterations were analyzed. The expressions of proinflammatory cytokines, including IL-1β, IL-6, TNF-α, and Gas6, Axl, STAT1, SOCS1, SOCS3 and the TLR/TRAF/NF-κB pathway were quantified using Western blot. Endogenous expressions of Gas6 and Axl decreased significantly by 24h after MCAO. rGas6 reduced brain infarction and improved neurologic deficits scores, and increased expression of Axl and decreased the expressions of TRAF3, TRAF6 and inflammatory factors IL-1β, IL-6, and TNF-α. Four weeks after MCAO, rGas6 improved long-term neurological behavior and memory. Inhibition of the Axl/TLR/TRAF/NF-κB pathway reversed the brain protection by rGas6. rGas6 reduced the neurological deficits by inhibiting neuroinflammation via the TLR/TRAF/NF-κB signaling pathway. rGas6 can be used as potential treatment to ischemic stroke. •Endogenous Gas6 and Axl decreased significantly at 24h after MCAO.•Recombinant Gas6 reduced brain infarction and improved neurologic deficits scores.•Recombinant Gas6 increased expression of Axl and decreased IL-1β, IL-6, TNF-α.•Recombinant Gas6 inhibited neuroinflammation via TLR/TRAF/NF-κB signaling pathway.