Low dose chidamide promotes inhibitory Fcγ receptorIIb expression on monocytes in ITP: A translational study of human ITP samples and ITP murine models
Hongyu Zhao, Wenjing Liu, Haoyi Wang, Daqi Li, Chen Su, Meili Sun, Xinguang Liu, Lu Sun, Juan Wang, Xiaodong Qiu, Guihuan Li, Meijuan Xue, Guohai Su, Ming Hou, Yu HouBackground
Downregulated inhibitory FcγRIIb promotes macrophage phagocytosis of antibody-opsonized platelets and drives immune thrombocytopenia (ITP), but the mechanism remains unclear.
Objectives
This translational study integrating human samples, cellular experiments and animal models aimed to explore whether ITP patients had aberrant histone acetylation level in FcγRIIb gene and how to alter the Fcγ receptor imbalance on monocytes.
Design
Monocytes from ITP patients are cultured with low-dose Chidamide. Low-dose Chidamide is tested in ITP mouse models to assess its regulation of monocyte FcγRIIb in vitro and in vivo.
Methods
Flow cytometry and qPCR detect FcγR expression in ITP patients. ChIP-seq assesses histone acetylation of the FcγRIIb gene. Lentiviral interference to verify that low-dose Chidamide treats ITP via upregulating FcγRIIb.
Results
Low-dose Chidamide elevated FcγRIIb mRNA and protein without markedly altering FcγRI or FcγRIII. Upregulated FcγRIIb substantially suppressed monocyte/macrophage phagocytosis. Chidamide also increased monocyte FcγRIIb in ITP mouse models. ChIP-seq revealed reduced histone acetylation at the FcγRIIb locus in ITP patients versus healthy controls. Chidamide restored H3K27 acetylation of FcγRIIb, boosted its transcription and impaired macrophage phagocytosis. FcγRIIb blockade abolished the therapeutic benefit of this HDAC inhibitor in ITP.
Conclusion
FcγRIIb gene histone acetylation was reduced in ITP patients compared with healthy controls, resulting in downregulated FcγRIIb expression. Low-dose Chidamide restored histone acetylation at the FcγRIIb locus, elevated FcγRIIb-positive monocytes, reversed FcγR imbalance, and normalized excessive monocyte phagocytosis in ITP.