Tomentosin suppressed M1 polarization via increasing MERTK activation mediated by regulation of GAS6

Ethnopharmacological relevance: Rheumatoid arthritis (RA) is characterized by chronic arthritis, which is accompanied by systemic involvement of multiple systems. The effect of Xanthium sibiricum Patrin ex Widder (X. sibiricum) on arthritis has been reported. Tomentosin is one of the sesquiterpene lactones isolated from X. sibiricum. Though the anti-inflammatory activity of tomentosin has been reported, the possible relationship of this effect to improving arthritis symptoms and its specific mechanism remain to be clarified.

Aim of the study: To investigate the effect of tomentosin in collagen-induced arthritis (CIA) mice and reveal its underlying mechanism.

Materials and methods: In vivo, tomentosin (10, 20 or 40 mg/kg) was given to CIA mice, to evaluate its therapeutic effect and anti-inflammatory activity. In vitro, THP-1-derived macrophages were used to verify the effect of tomentosin on inflammation. Then, molecular docking and experiments in vitro was conducted to predict and explore the mechanism of tomentosin inhibiting inflammation.

Results: Tomentosin attenuated the severity of arthritis in CIA mice, which was evidenced by the swelling of the hind paws, arthritis scores, and pathological changes. Particularly, tomentosin effectively reduced the ratio of M1 macrophage and TNF-α levels in vitro and vivo. Then, molecular docking and experiments in vitro was carried out, indicating that tomentosin inhibited M1 polarization and TNF-α levels accompanied by the increase of MERTK and up-regulated GAS6 levels. Moreover, it has been proved that GAS6 was necessary for MERTK activation and tomentosin could up-regulate GAS6 levels effectively in transwell system. Further mechanistic studies revealed that tomentosin suppressed M1 polarization via increasing MERTK activation mediated by regulation of GAS6 in transwell system.

Conclusion: Tomentosin relieved the severity of CIA mice by inhibiting M1 polarization. Furthermore, tomentosin suppressed M1 polarization via increasing MERTK activation mediated by regulation of GAS6.

Collagen-induced arthritis; GAS6; Inflammation; MERTK; Macrophages; Traditional Chinese medicine.