Bilirubin Alleviates Spinal Cord Injury by Enhancing SOCS3-Mediated Anti-Inflammatory Effects via Gas6-Axl Signaling.

BACKGROUND: Many studies have emphasized the role of microglia-mediated neuroinflammation in spinal cord injury (SCI); however, effective clinical targets remain elusive. The growth arrest-specific 6 (Gas6)/Axl receptor tyrosine kinase (Axl) signaling pathway has been implicated in reducing inflammation, promoting tissue repair, and functional recovery. Here, we elucidate the importance of the Gas6-Axl signaling pathway in SCI repair and evaluate the role of bilirubin in modulating Gas6-Axl signaling after SCI. METHODS: SCI mice model was used to investigate the effects of bilirubin treatment on inflammation and motor function recovery. Additionally, Gas6-deficient (Gas6(-)/(-)) mice and wild-type (WT) mice were employed to examine the role of Gas6-Axl signaling in SCI recovery. Microglial cells were cultured to assess the effects of bilirubin on the activation of the Gas6-Axl-SOCS3 signaling pathway. RESULTS: Gas6(-)/(-) mice exhibited increased mortality, severe locomotor deficits, and impaired neuromuscular activity compared to WT mice. Bilirubin treatment in SCI models facilitated recovery by upregulating Gas6-Axl signaling, which in turn enhanced SOCS3 expression and suppressed the expression of pro-inflammatory mediators such as IL-1β and MMP-9. Furthermore, bilirubin treatment reduced microglial activation, highlighting its neuroprotective and anti-inflammatory properties. CONCLUSIONS: This study underscores the importance of the Gas6-Axl-SOCS3 axis in regulating functional recovery and inflammation after SCI. Activation of the Gas6-Axl pathway, particularly when combined with bilirubin treatment, represents a promising therapeutic strategy for mitigating SCI-induced damage and improving functional outcomes. Given their central role in both the pathogenesis and resolution of SCI, bilirubin treatment emerges as a promising clinical therapeutic drug for SCI.