A novel chrysin thiazole derivative polarizes macrophages to an M1 phenotype via targeting TLR4

Tumor-associated macrophages (TAMs) are an important cause of tumorigenesis and tumor development. M2 macrophages can promote tumor growth while M1 macrophages kill tumor cells, therefore, polarizing macrophages to achieve a functional M1 phenotype could effectively play its anti-tumor role. In the current study, we synthesized a novel chrysin derivative which is termed as ChR-TD. And we found ChR-TD might be a ligand of TLR4 that polarized the TAMs towards M1 phenotype and played its anti-tumor role. Further study indicated that ChR-TD reprogrammed the macrophages into an M1 phenotype via TLR4 activation. Moreover, ChR-TD activated TLR4/NF-kappa B signaling pathway and promoted the NF-kappa B/p65 translocated into the nuclear, leading to the activation of NF-kappa B and proinflammatory cytokines release. In addition, type I interferon signaling was also activated by ChR-TD, leading to the expressions of IFN-alpha and IFN-beta and its targeted genes NOS2, MCP-1 and IP-10 were significantly increased in macro-phages. Importantly, these effects were disturbed in TLR4(-/-) macro- phages, which are constructed by using CRISPR/Cas9 system. And the molecule docking simulation further indicated that ChR-TD could bind to TLR4 and might be a ligand of TLR4. Hence, these findings suggested that ChR-TD might be a ligand of TLR4 and can be used as a potential lead compound for tumors treatment.