Resveratrol increases efferocytosis via both Mertk-GAS6/PROS and Integrin-TG2-Mfge8 pathway

Abstract The impairment of clearance of apoptotic cells (efferocytosis) leads to local inflammatory response and tissue damage. Recent studies have found the defective mechanism in apoptotic clearance is related to the pathogenesis of autoimmune disease such as systemic lupus erythematosus (SLE). There have been many studies about the positive effects of resveratrol, including anti-diabetic effect, anti-inflammation, anti-oxidation, and anti-aging. However, the effect of resveratrol on clearance of apoptotic cells by macrophage is still remaining unknown. We investigated the effects of resveratrol on efferocytosis. Methods HaCaT and the thymocytes from C57BL/6 were induced apoptosis by UVB and stained with Deep red mitotracker. CFSE stained RAW 264.7 was treated with 1, 5, 10 mM resveratrol for 24 hrs then co-cultured with apoptotic HaCaT to investigate the effect of resveratrol on efferocytosis. To measure the mRNA expression, RAW 264.7 RNA was extracted by RNAzol and then progress reverse transcription and real time PCR. Results The results showed that 10 mM resveratrol increased efferocytosis. We further investigated the molecular mechanism of efferocytosis. We found that ITGa5, ITGb3, TG2, Mfge8, and Mertk mRNA were up-regulated by resveratrol after co-cultured with or without apoptotic HaCaT; GAS6 and PROS mRNA expression were up-regulated by resveratrol only after co-cultured with apoptotic cells. The results revealed that resveratrol might enhance efferocytosis by regulating Mfge8-Integrin and GAS6/PROS-Mertk signaling pathway. Conclusion Resveratrol enhances efferocytosis via both Mertk-GAS6/PROS and Integrin-TG2-Mfge8 pathway. Resveratrol may be used for the therapy of autoimmune diseases.