AXL-Induced Autophagy mitigates experimental autoimmune encephalomyelitis by suppressing microglial inflammation via the PI3K/AKT/mTOR signaling pathway

It is widely believed that the most common pathological changes in multiple sclerosis (MS) are neuroinflammatory demyelination and neuronal degeneration (Chase Huizar et al., 2020, Filippi et al., 2018, Paunovic et al., 2018). As sentinels of immune surveillance in the central nervous system (CNS), microglia initiate immune responses through pattern recognition receptors (PRRs) on the cell membrane to protect the CNS from pathogens (Kong et al., 2014, Li et al., 2021). Current evidence suggests that cytokines released by microglia in the early stage could enhance the pro-inflammatory environment (Olcum et al., 2020). Meanwhile, the TAM (Tyro3-/-Axl-/-Mertk-/-) receptor family negatively regulates the inflammatory response, which clears the myelin fragments and inhibits the inflammatory response (Mostafa et al., 2022). Studies have demonstrated that mice lacking TAM receptors (Tyro3, Axl, Mer) are prone to developing lymphoproliferative diseases (Cohen et al., 2002, Lu and Lemke, 2001). Furthermore, it has been shown that the binding of AXL to Gas6 ligands can exert a negative regulatory effect on liver inflammation (Han et al., 2016). Besides, the knockout of the Gas6 gene (Gas6-/-) in an ischemia-reperfusion injury model resulted in a more severe inflammatory response (Llacuna et al., 2010). In a copper-induced demyelination model, Gas6-/- mice showed more serious demyelination damage (Bellan et al., 2016, Binder et al., 2008). Furthermore, treatment with the Gas6 recombinant protein could alleviate demyelination (Tsiperson et al., 2010). In the experimental autoimmune encephalomyelitis (EAE) mice model, during the acute phase, we found that the upregulation of AXL expression increased the levels of anti-inflammatory factor SCOS1/3 through negative feedback of TLR3/4 and JAK/STAT3 signal pathways (Li et al., 2020). In addition, it has been reported that TAM receptors can regulate the expression of autophagy in tumors and neurodegenerative diseases (Qi et al., 2021).

Recent studies have shown that the induction of autophagy is related to the receptor tyrosine kinase (TAM family) on the cell membrane of microglia and astrocytes (Goudarzi et al., 2020). Moreover, Mer, one of the TAM families, regulates the polarization of microglia in spinal cord injury models, promotes the transformation from M1 to M2, and reduces the inflammatory response (Wu et al., 2021). Consistently, our previous studies found that the expression of AXL was increased in the EAE model, and the symptoms could be alleviated by treatment with the classic autophagy agonist rapamycin (Li et al., 2020). However, the mechanism of AXL and autophagy in MS remains unclear.

In summary, this study sought to investigate the impact of AXL on the autophagy of microglia and explore its underlying mechanisms in the EAE model.

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