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    • The mechanism by which Gas prevents inflammation has been

    2023-01-24

    The mechanism by which Gas6 prevents inflammation has been reported to be via inhibition of Toll-Like receptors (TLRs) signaling (Cui et al., 2016). After injury, TLRs become stimulated, leading to downstream activation of TRAF3 and TRAF6 and translocation of several transcription factors, such as IRF3 and NF-κB. The latter which is crucial for inflammation after stroke, leading to production of cytokines (O'Neill, 2007). Our findings provide additional support for the TLR/TRAF/NF-κB signaling for cytokine production; after MCAO, TRAF3 and TRAF6 are increased followed by the upregulation of NF-κB, IL-1β, IL-6 and TNF-α from 6h to 72h. In order to prevent the development of autoimmune responses and limit the detrimental effects of chronic inflammation, TLRs upregulate TAMs via the type I interferon receptor-STAT1 pathway (O'Neill, 2007, Rothlin et al., 2015). With the upregulation of TAMs, Gas6, their ligand, can activate STAT1, and downstream production of SOCS1 and SOCS3 (Lemke and Rothlin, 2008, Rothlin et al., 2015). SOCS1 and SOCS3 then inhibit TLRs signaling by targeting Mal, TRAF3, and TRAF6 (O'Neill, 2007). In this study, Axl and STAT1 protein 2-deoxy-d-glucose and phosphorylation increased after administration of exogenous rGas6 after MCAO in rats, leading to increased SOCS1 and SOCS3 expression, and decreased expressions of TRAF3, TRAF6, and proinflammatory cytokines IL-1β, IL-6 and TNF-α. Inhibition of Axl by R428 or silencing of SCOS1 and SOCS3 by siRNA abolished the beneficial effects of rGas6 by allowing the expressions of TRAF3 and TRAF6 in the TLR/TRAF/NF-κB pathway, causing greater IL-1β, IL-6 and TNF-α. These findings further support the role of TAM receptors (specifically Axl) suppress TLRs signaling pathways to prevent excessive inflammation, restoring homeostatic balance (Rothlin et al., 2015, Fourgeaud et al., 2016). To date, several anti-inflammatory agents with promising experimental findings had failed to translate as therapies for stroke. Despite reduced enthusiasm for anti-inflammatory agents for stroke, there are a number of ongoing clinical trials investigating anti-inflammatory agents. Furthermore, the past limited-success of anti-inflammatory agents does not alter the enthusiasm for Axl signaling. In this study, we found that rGas6 can not only reduce neuro-inflammation, but also decrease infarct volume. Although this study focused on Axl signaling for anti-inflammation, rGas6 may also trigger additional signaling, leading to reduced neuronal apoptosis (see the Limitations and Future Directions section below). In support of the potential role of Gas6 in neuronal cell survival, Gas6 has been reported to have pleotropic effects, including growth and cell survival, tissue repair, and development, in addition to its anti-inflammatory role (Llacuna et al., 2010).
    Conclusion
    Conflicts of interest
    Acknowledgments This work was partially supported by the National Institutes of Health [grant numbers: NS081740 and NS082184].
    Receptor Tyrosine kinases (RTKs) are high affinity cell surface receptors involved in crucial signaling pathways such as cell proliferation, migration, differentiation and cell survival. Dysregulations of the activity of these RTKs (mostly due to mutation or kinase overactivation) are observed in multiple diseases and especially in cancer. Targeting RTK signaling pathways is a targeted therapy highly developed and promising to fight cancer. AXL also called UFO is a RTK belonging to the TAM family as MER and TYRO-3. Like other RTK, AXL activation leads to signal transduction cascades with activated signaling pathways such as PI3K/AKT, mitogen-activated protein kinase (MAPK) or STAT. With its involvement in cellular processes such as cell proliferation, migration, adhesion and cell survival, AXL is emerging as a validated therapeutic target for several diseases and more particularly in oncology. AXL is expressed in a wide range of tumor types, both liquid and solid. Overexpression and/or overactivation of AXL have been correlated to tumor stage and aggressiveness, drug-resistance and considered as a poor prognostic factor in most types of cancer. Since the last decade, AXL appears as a crucial target to inhibit in order to stop cancer progression.