Jieduquyuziyin prescription alleviates lupus by upregulating GDF15 to inhibit M1 macrophage polarization.

BACKGROUND: Jieduquyuziyin prescription (JP) was clinically effective for the treatment of systemic lupus erythematosus (SLE), with increasing evidence supporting its immunomodulatory effects. Although growth differentiation factor 15 (GDF15) has been implicated in the development of SLE, whether GDF15 mediates the therapeutic action of JP remains to be determined. PURPOSE: This research aims to identify GDF15 as a specific molecular target mediating the JP's pharmacological activity against SLE. METHODS: Serum and renal GDF15 levels were measured by ELISA and western blot, respectively, in MRL/lpr and MRL/Mpj mice at 12, 16, and 20 weeks of age. To determine whether GDF15 mediates the therapeutic effects of JP in lupus, we utilized GDF15 knockdown in RAW264.7 cells and bone marrow derived macrophages (BMDMs), and GDF15-knockout lupus mice. UPLC-MS/MS was employed to identify the main constituents of JP decoction and serum, and the major active components were subsequently validated for their effects on GDF15 expression in RAW264.7 cells and BMDMs. RESULTS: During disease progression in MRL/lpr mice, serum GDF15 levels decreased and renal GDF15 expression fluctuated, while exogenous GDF15 protein alleviated lupus manifestations, suggesting that GDF15 was closely linked to lupus pathogenesis. In addition, JP upregulated GDF15 more strongly than prednisone, leading to increased serum levels and renal expression of GDF15. Genetic ablation of GDF15 partially abolished the beneficial effects of JP on lupus. Mechanistically, JP serum strongly inhibited M1 macrophage polarization of RAW246.7 cells and BMDMs, an effect that was eliminated by GDF15 silencing or GDF15 knock-out. Furthermore, active ingredients of JP, including paeoniflorin, glycyrrhizic acid, and turanose, also inhibited M1 polarization by upregulating GDF15. CONCLUSION: These findings identify GDF15 as a key mediator and potential therapeutic target of SLE, and provided experimental evidence supporting JP as a treatment for SLE.