OC 05.4 - The Adiponectin Receptor Agonist (AdipoRon) Ameliorates Immune Thrombocytopenia through Enhancing Chaperone Mediated Autophagy in Macrophages

Background: Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease. Macrophage plays vital roles in platelet destruction and inflammatory responses in the pathogenesis of ITP. Our previous studies suggested that lipid metabolism disorders were frequently accompanied with ITP. Adiponectin is an abundant adipokine participating in lipid metabolism, and exerts pleiotropic functions in immune regulation. Chaperone mediated autophagy (CMA) is an autophagy that selectively degrade chaperone binding proteins in lysosome, and is reported to be related to lipid metabolism and inflammation.

Aims: To investigate the regulatory effects of AdipoRon, an adiponectin receptor agonist, on ITP, and further understand the correlation of lipid metabolism and ITP.

Methods: Macrophages derived from THP-1 cell line or peripheral blood mononuclear cells (PBMC) from ITP patients were treated with 20 μm AdipoRon or vehicle. Flow cytometry, quantitative PCR and immunofluorescence were employed to evaluate the polarization, activation and phagocytosis functions of macrophages. Oil red staining was used to exhibit the accumulation of lipid in macrophages. SiRNA of LAMP2A was transfected into macrophages to block CMA. We also established the passive and active ITP murine models to explore the effects of AdipoRon in vivo.

Results: ITP patients had higher levels of adiponectin in plasma compared to controls. AdipoRon could reduce the lipid accumulation, M1 polarization, and platelet phagocytosis in macrophages. (Fig 1). LAMP2A, a key protein of CMA, was increased in macrophages after treatment of AdipoRon, and the knock down of LAMP2A blocked the anti-inflammatory effects of AdipoRon in macrophages. In ITP murine models, mice treated with AdipoRon showed higher platelet counts compared to the control ITP mice. And M1 polarization of macrophages from spleen, liver and bone marrow was also inhibited after treated with AdipoRon (Fig 2).

Conclusion(s): AdipoRon exert beneficial effects on ITP through modulating the polarization and platelet phagocytosis of macrophage in a CMA dependent pathway.