Thromb Haemost 2021; 121(06): 767-781
DOI: 10.1055/s-0040-1722186
Cellular Haemostasis and Platelets

Tumor Necrosis Factor-α Blockade Corrects Monocyte/Macrophage Imbalance in Primary Immune Thrombocytopenia

Yajing Zhao
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Pengcheng Xu
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Li Guo
2  Molecular Medicine Program, University of Utah, Salt Lake City, Utah, United States
,
Haoyi Wang
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Yanan Min
3  Department of Haematology, Affiliated Hospital of Jining Medical University, Jining, China
,
Qi Feng
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Yu Hou
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Tao Sun
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Guosheng Li
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Xuebin Ji
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Jihua Qiu
4  Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Jun Peng
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
5  Shandong Provincial Key Laboratory of Immunohaematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
6  Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Xinguang Liu
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
,
Ming Hou
1  Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
5  Shandong Provincial Key Laboratory of Immunohaematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
6  Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
7  Department of Science and Technology of Shandong Province, Leading Research Group of Scientific Innovation, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
› Author Affiliations
Funding This work was supported by grants from National Natural Science Foundation of China (NSFC, Nos. 81770114, 81973994, 82000123, 81770133, 81700113, 81800112, 81900121, 81873425, 81800157), Leading Research Group of Scientific Innovation, State Key Clinical Specialty of China for Haematological Diseases, Taishan Scholar of Shandong Province, Clinical Science and Technology Innovation Program of Jinan Science and Technology Project (201704085), Major Research Plan of Natural Science Foundation of Shandong Province (2019GSF108240), and Junior Taishan Scholar of Shandong Province.

Abstract

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. Monocytes and macrophages are the major cells involved in autoantibody-mediated platelet clearance in ITP. In the present study, we found increased percentages of peripheral blood proinflammatory CD16+ monocytes and elevated frequencies of splenic tumor necrosis factor-α (TNF-α)-expressing macrophages in ITP patients compared with healthy controls. Concurrently, we observed elevated TNF-α secretion in plasma as well as higher TNF-α mRNA expression in total peripheral blood mononuclear cells and CD14+ monocytes of ITP patients. Of note, in vitro TNF-α blockade with neutralizing antibody remarkably reduced polarization to M1 macrophages by inhibiting the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, TNF-α blockade dampened macrophage phagocytosis and T cell stimulatory capacity. Finally, in passive and active murine models of ITP, anti-TNF-α therapy reduced the number of nonclassical monocytes and M1 macrophages, ameliorated the retention of platelets in spleen and liver, and increased the platelet count of ITP mice. Taken together, TNF-α blockade decreased the number and function of proinflammatory subsets of monocytes and macrophages by inhibiting the NF-κB signaling pathway, leading to remarkable attenuation of antibody-mediated platelet destruction. Thus, TNF-α blockade may be a promising therapeutic strategy for the management of ITP.

Authors' Contributions

Y.Z. and X.L. performed the research, analyzed the data, and wrote the manuscript; P.X., H.W., and G.L. performed the research and analyzed the data; L.G., Y.M., T.S., J.Q., X.J., Q.F., Y.H., and J.P. evaluated the data and corrected the manuscript; X.L. and M.H. designed and reviewed the work, and all authors read and edited the manuscript.


Supplementary Material



Publication History

Received: 25 May 2020

Accepted: 11 November 2020

Publication Date:
14 January 2021 (online)

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