Low‐dose decitabine promotes M2 macrophage polarization in patients with primary immune thrombocytopenia via enhancing KLF4 binding to PPARγ promoter

Author:

Shao Xia1,Xu Pengcheng12,Ji Lili2,Wu Boting3,Zhan Yanxia2,Zhuang Xibing12,Ou Yang12,Hua Fanli2,Sun Lihua2,Li Feng2,Wang Xiangdong14,Chen Hao5ORCID,Cheng Yunfeng124ORCID

Affiliation:

1. Center for Tumor Diagnosis and Therapy Jinshan Hospital Fudan University Shanghai China

2. Department of Hematology Zhongshan Hospital Qingpu Branch Fudan University Shanghai China

3. Department of Transfusion Medicine Zhongshan Hospital Qingpu Branch Fudan University Shanghai China

4. Institute of Clinical Science Zhongshan Hospital Fudan University Shanghai China

5. Department of Thoracic Surgery Zhongshan‐Xuhui Hospital Fudan University Shanghai China

Abstract

BackgroundThe first‐line therapy is effective for the treatment of primary immune thrombocytopenia (ITP); however, maintaining the long‐term responses remains challenging. Low‐dose decitabine (DAC) has been adopted to treat refractory ITP, while its role in macrophage polarization has not been fully understood. We aimed to investigate the mechanistic role of DAC in M2 macrophage polarization and evaluated its therapeutic effect in ITP.MethodsThe M2 monocytes were identified by flow cytometry from peripheral blood mononuclear cells in healthy controls (HCs) and ITP patients. The expression of PPARγ, Arg‐1, DNMT3b and NLRP3, together with IL‐10 plasma levels was measured to examine its function. Bisulfite‐sequencing PCR was used to evaluate the methylation status of PPARγ promoter, and the binding affinity of KLF4 was measured by Cut&Tag. A sh‐PPARγ THP‐1 cell line was created to verify if low‐dose DAC‐modulated M2 macrophage polarization was PPARγ‐dependent. The passive ITP models were used to investigate the therapeutic effects of low‐dose DAC and its role in modulating polarization and immunomodulatory function of macrophages. NLRP3 inflammasome and reactive oxygen species were also tested to understand the downstream of PPARγ.ResultsThe M2 monocytes with impaired immunoregulation were observed in ITP. After high‐dose dexamethasone (HD‐DXM) treatment, M2 monocytes increased significantly with the elevated expression of PPARγ, Arg‐1 and IL‐10 in CR patients. Low‐dose DAC promoted M2 macrophage polarization in a PPARγ‐dependent way via demethylating the promoter of PPARγ, especially the KLF4 binding sites. Low‐dose DAC alleviated ITP mice by restoring the M1/M2 balance and fine‐tuning immunomodulatory function of macrophages. The downstream of the PPARγ modulation of M2 macrophage polarization might physiologically antagonize NLRP3 inflammasome.ConclusionsLow‐dose DAC promoted M2 macrophage polarization due to the demethylation within the promoter of PPARγ, thus enhanced the KLF4 binding affinity in ITP.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Molecular Medicine,Medicine (miscellaneous)

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