Download PDF
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.
› Further Information
Also available at
    Permissions and Reprints

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.

Keywords

immune thrombocytopenia - tumor necrosis factor-α - monocytes - macrophages

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

Article published online:
14 January 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Provan D, Stasi R, Newland AC. et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115 (02) 168-186
    CrossrefPubMedGoogle Scholar
  • 2 Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood 2017; 129 (21) 2829-2835
    CrossrefPubMedGoogle Scholar
  • 3 Provan D, Arnold DM, Bussel JB. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 2019; 3 (22) 3780-3817
    CrossrefPubMedGoogle Scholar
  • 4 Vianelli N, Galli M, de Vivo A. et al; Gruppo Italiano per lo Studio delle Malattie Ematologiche dell'Adulto. Efficacy and safety of splenectomy in immune thrombocytopenic purpura: long-term results of 402 cases. Haematologica 2005; 90 (01) 72-77
    PubMedGoogle Scholar
  • 5 Cuker A, Neunert CE. How I treat refractory immune thrombocytopenia. Blood 2016; 128 (12) 1547-1554
    CrossrefPubMedGoogle Scholar
  • 6 Miltiadous O, Hou M, Bussel JB. Identifying and treating refractory ITP: difficulty in diagnosis and role of combination treatment. Blood 2020; 135 (07) 472-490
    CrossrefPubMedGoogle Scholar
  • 7 Chow L, Aslam R, Speck ER. et al. A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy. Blood 2010; 115 (06) 1247-1253
    CrossrefPubMedGoogle Scholar
  • 8 Audia S, Mahévas M, Samson M, Godeau B, Bonnotte B. Pathogenesis of immune thrombocytopenia. Autoimmun Rev 2017; 16 (06) 620-632
    CrossrefPubMedGoogle Scholar
  • 9 Chaturvedi S, Arnold DM, McCrae KR. Splenectomy for immune thrombocytopenia: down but not out. Blood 2018; 131 (11) 1172-1182
    CrossrefPubMedGoogle Scholar
  • 10 Tolouei Semnani R, Moore V, Bennuru S. et al. Human monocyte subsets at homeostasis and their perturbation in numbers and function in filarial infection. Infect Immun 2014; 82 (11) 4438-4446
    CrossrefPubMedGoogle Scholar
  • 11 Ziegler-Heitbrock L. Reprint of: monocyte subsets in man and other species. Cell Immunol 2014; 291 (1–2): 11-15
    CrossrefPubMedGoogle Scholar
  • 12 Stansfield BK, Ingram DA. Clinical significance of monocyte heterogeneity. Clin Transl Med 2015; 4: 5
    CrossrefPubMedGoogle Scholar
  • 13 Sprangers S, de Vries TJ, Everts V. Monocyte heterogeneity: consequences for monocyte-derived immune cells. J Immunol Res 2016; 2016: 1475435
    CrossrefPubMedGoogle Scholar
  • 14 Zhong H, Bao W, Li X. et al. CD16+ monocytes control T-cell subset development in immune thrombocytopenia. Blood 2012; 120 (16) 3326-3335
    CrossrefPubMedGoogle Scholar
  • 15 Tacke F, Randolph GJ. Migratory fate and differentiation of blood monocyte subsets. Immunobiology 2006; 211 (6–8): 609-618
    CrossrefPubMedGoogle Scholar
  • 16 Ziegler-Heitbrock L. The CD14+ CD16+ blood monocytes: their role in infection and inflammation. J Leukoc Biol 2007; 81 (03) 584-592
    CrossrefPubMedGoogle Scholar
  • 17 Liu YC, Zou XB, Chai YF, Yao YM. Macrophage polarization in inflammatory diseases. Int J Biol Sci 2014; 10 (05) 520-529
    CrossrefPubMedGoogle Scholar
  • 18 Parisi L, Gini E, Baci D. et al. Macrophage polarization in chronic inflammatory diseases: killers or builders?. J Immunol Res 2018; 2018: 8917804
    CrossrefPubMedGoogle Scholar
  • 19 Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol 2016; 12 (08) 472-485
    CrossrefPubMedGoogle Scholar
  • 20 Feng Q, Xu M, Yu YY. et al. High-dose dexamethasone or all-trans-retinoic acid restores the balance of macrophages towards M2 in immune thrombocytopenia. J Thromb Haemost 2017; 15 (09) 1845-1858
    CrossrefPubMedGoogle Scholar
  • 21 Parameswaran N, Patial S. Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr 2010; 20 (02) 87-103
    CrossrefPubMedGoogle Scholar
  • 22 Scull CM, Hays WD, Fischer TH. Macrophage pro-inflammatory cytokine secretion is enhanced following interaction with autologous platelets. J Inflamm (Lond) 2010; 7: 53
    CrossrefPubMedGoogle Scholar
  • 23 Hess DJ, Henry-Stanley MJ, Bendel CM, Zhang B, Johnson MA, Wells CL. Escherichia coli and TNF-alpha modulate macrophage phagocytosis of Candida glabrata. J Surg Res 2009; 155 (02) 217-224
    CrossrefPubMedGoogle Scholar
  • 24 Coelho HC, Lopes SC, Pimentel JP. et al. Thrombocytopenia in Plasmodium vivax malaria is related to platelets phagocytosis. PLoS One 2013; 8 (05) e63410
    CrossrefPubMedGoogle Scholar
  • 25 Radner H, Aletaha D. Anti-TNF in rheumatoid arthritis: an overview. Wien Med Wochenschr 2015; 165 (1–2): 3-9
    CrossrefPubMedGoogle Scholar
  • 26 Solberg SM, Sandvik LF, Eidsheim M, Jonsson R, Bryceson YT, Appel S. Serum cytokine measurements and biological therapy of psoriasis - prospects for personalized treatment?. Scand J Immunol 2018; 88 (06) e12725
    CrossrefPubMedGoogle Scholar
  • 27 Culić S, Salamunić I, Konjevoda P, Dajak S, Pavelić J. Immune thrombocytopenia: serum cytokine levels in children and adults. Med Sci Monit 2013; 19: 797-801
    CrossrefPubMedGoogle Scholar
  • 28 Jernås M, Hou Y, Strömberg Célind F. et al. Differences in gene expression and cytokine levels between newly diagnosed and chronic pediatric ITP. Blood 2013; 122 (10) 1789-1792
    CrossrefPubMedGoogle Scholar
  • 29 Talaat RM, Elmaghraby AM, Barakat SS, El-Shahat M. Alterations in immune cell subsets and their cytokine secretion profile in childhood idiopathic thrombocytopenic purpura (ITP). Clin Exp Immunol 2014; 176 (02) 291-300
    CrossrefPubMedGoogle Scholar
  • 30 Doss GP, Agoramoorthy G, Chakraborty C. TNF/TNFR: drug target for autoimmune diseases and immune-mediated inflammatory diseases. Front Biosci 2014; 19: 1028-1040
    CrossrefPubMedGoogle Scholar
  • 31 Gerriets V, Bansal P, Goyal A. et al. Tumor Necrosis Factor Inhibitors. [Updated 2020 Jul 4]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2020. Accessed December 3, 2020 at: https://www.ncbi.nlm.nih.gov/books/NBK482425/
    Google Scholar
  • 32 Levin AD, Koelink PJ, Bloemendaal FM. et al. Autophagy contributes to the induction of anti-TNF induced macrophages. J Crohn's Colitis 2016; 10 (03) 323-329
    CrossrefPubMedGoogle Scholar
  • 33 Ceccarelli F, Massafra U, Perricone C. et al. Anti-TNF treatment response in rheumatoid arthritis patients with moderate disease activity: a prospective observational multicentre study (MODERATE). Clin Exp Rheumatol 2017; 35 (01) 24-32
    PubMedGoogle Scholar
  • 34 Verstockt B, Ferrante M, Vermeire S, Van Assche G. New treatment options for inflammatory bowel diseases. J Gastroenterol 2018; 53 (05) 585-590
    CrossrefPubMedGoogle Scholar
  • 35 McMinn Jr JR, Cohen S, Moore J. et al. Complete recovery from refractory immune thrombocytopenic purpura in three patients treated with etanercept. Am J Hematol 2003; 73 (02) 135-140
    CrossrefPubMedGoogle Scholar
  • 36 Litton G. Refractory idiopathic thrombocytopenic purpura treated with the soluble tumor necrosis factor receptor etanercept. Am J Hematol 2008; 83 (04) 344
    CrossrefPubMedGoogle Scholar
  • 37 Zhong H, Bussel J, Yazdanbakhsh K. In vitro TNF blockade enhances ex vivo expansion of regulatory T cells in patients with immune thrombocytopenia. Br J Haematol 2015; 168 (02) 274-283
    CrossrefPubMedGoogle Scholar
  • 38 Liu XG, Ma SH, Sun JZ. et al. High-dose dexamethasone shifts the balance of stimulatory and inhibitory Fcgamma receptors on monocytes in patients with primary immune thrombocytopenia. Blood 2011; 117 (06) 2061-2069
    CrossrefPubMedGoogle Scholar
  • 39 Liu XG, Liu S, Feng Q. et al. Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP. Blood 2016; 128 (06) 852-861
    CrossrefPubMedGoogle Scholar
  • 40 Amash A, Wang L, Wang Y. et al. CD44 antibody inhibition of macrophage phagocytosis targets Fcγ receptor- and complement receptor 3-dependent mechanisms. J Immunol 2016; 196 (08) 3331-3340
    CrossrefPubMedGoogle Scholar
  • 41 Yang Y, Zhang X, Zhang D. et al. Abnormal distribution and function of monocyte subsets in patients with primary immune thrombocytopenia. Clin Appl Thromb Hemost 2017; 23 (07) 786-792
    CrossrefPubMedGoogle Scholar
  • 42 Guo L, Kapur R, Aslam R. et al. Antiplatelet antibody-induced thrombocytopenia does not correlate with megakaryocyte abnormalities in murine immune thrombocytopenia. Scand J Immunol 2018; 88 (01) e12678
    CrossrefPubMedGoogle Scholar
  • 43 Semple JW, Bruce S, Freedman J. Suppressed natural killer cell activity in patients with chronic autoimmune thrombocytopenic purpura. Am J Hematol 1991; 37 (04) 258-262
    CrossrefPubMedGoogle Scholar
  • 44 Olsson B, Andersson PO, Jernås M. et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med 2003; 9 (09) 1123-1124
    CrossrefPubMedGoogle Scholar
  • 45 Takahashi N, Saitoh T, Gotoh N. et al. The cytokine polymorphisms affecting Th1/Th2 increase the susceptibility to, and severity of, chronic ITP. BMC Immunol 2017; 18 (01) 26
    CrossrefPubMedGoogle Scholar
  • 46 Zhang J, Zhang Q, Li Y. et al. Immune dysregulation in primary immune thrombocytopenia patients. Hematology 2018; 23 (08) 510-516
    CrossrefPubMedGoogle Scholar
  • 47 Nocturne G, Boudaoud S, Ly B, Pascaud J, Paoletti A, Mariette X. Impact of anti-TNF therapy on NK cells function and on immunosurveillance against B-cell lymphomas. J Autoimmun 2017; 80: 56-64
    CrossrefPubMedGoogle Scholar
  • 48 Kapur R, Aslam R, Kim M. et al. Thymic-derived tolerizing dendritic cells are upregulated in the spleen upon treatment with intravenous immunoglobulin in a murine model of immune thrombocytopenia. Platelets 2017; 28 (05) 521-524
    CrossrefPubMedGoogle Scholar
  • 49 Vos AC, Wildenberg ME, Duijvestein M, Verhaar AP, van den Brink GR, Hommes DW. Anti-tumor necrosis factor-α antibodies induce regulatory macrophages in an Fc region-dependent manner. Gastroenterology 2011; 140 (01) 221-230
    CrossrefPubMedGoogle Scholar