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CC BY-NC-ND 4.0 · Thromb Haemost 2019; 119(02): 234-245
DOI: 10.1055/s-0038-1676796
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Macrophage Polarization is Deregulated in Haemophilia

Lynn M. Knowles
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Saarland University Faculty of Medicine, Saarland University, Homburg, Germany
,
Daniela Kagiri
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Saarland University Faculty of Medicine, Saarland University, Homburg, Germany
,
Martin Bernard
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Saarland University Faculty of Medicine, Saarland University, Homburg, Germany
,
Eva C. Schwarz
2   Department of Biophysics, CIPMM, Saarland University Faculty of Medicine, Saarland University, Homburg, Germany
,
Hermann Eichler
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Saarland University Faculty of Medicine, Saarland University, Homburg, Germany
,
Jan Pilch
1   Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Saarland University Faculty of Medicine, Saarland University, Homburg, Germany
› Institutsangaben Funding This work was supported by CSL Behring GmbH (J.P. and H.E.), the Pfizer ASPIRE Award (J.P.) and the Hans Egli Stipend of the Gesellschaft für Thrombose- und Hämostaseforschung e.V. (L.M.K.).
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Publikationsverlauf

12. Juni 2018

10. November 2018

Publikationsdatum:
16. Januar 2019 (online)

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Abstract

Macrophages make important contributions to inflammation and wound healing. We show here that macrophage polarization is deregulated in haemophilia in response to macrophage colony-stimulating factor (M-CSF) and partially in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). As a result, haemophilia macrophages exhibit a specific impairment of M-CSF-mediated functions involved in wound healing such as clot invasion and phagocytosis. Haemophilia monocytes express reduced amounts of the receptors for M-CSF and GM-CSF, which correlates with a failure to express tumour necrosis factor α (TNFα) and CD163 in M-CSF-treated haemophilia macrophages and reduced expression of TNFα and CD206 after treatment with GM-CSF. Protein expression in response to M-CSF was regained with respect to CD163 and CD206 after embedding haemophilia monocytes in clotted plasma suggesting that a functioning coagulation system has positive effects on macrophage M2 polarization. Mimicking the functional deficits of haemophilia macrophages in normal macrophages was possible by adding leptin, which we found to be elevated in the blood of haemophilia patients, to a monocyte cell line. The increase of leptin occurred in conjunction with C-reactive protein in a body mass index-controlled cohort suggesting that haemophilia patients harbour chronic low-grade inflammation. Together, our data indicate that impaired clotting in haemophilia patients leads to increased inflammation and a deregulation in macrophage differentiation, which may explain the commonly observed deficits in wound healing and tissue regeneration.

Keywords

haemophilia - macrophage - fibrin

Authors' Contributions

L.M. Knowles, H. Eichler and J. Pilch designed the research; L.M. Knowles, D. Lessig and M. Bernard performed the experiments; E. Schwarz contributed to methods and reagents; L.M. Knowles and J. Pilch analysed the data; and L.M. Knowles and J. Pilch wrote the manuscript.


Supplementary Material

 

  • References

  • 1 Monroe DM, Hoffman M. The clotting system - a major player in wound healing. Haemophilia 2012; 18 (Suppl. 05) 11-16
    PubMedGoogle Scholar
  • 2 Hoffman M, Harger A, Lenkowski A, Hedner U, Roberts HR, Monroe DM. Cutaneous wound healing is impaired in hemophilia B. Blood 2006; 108 (09) 3053-3060
    CrossrefPubMedGoogle Scholar
  • 3 Aronstam A, Rainsford SG, Painter MJ. Patterns of bleeding in adolescents with severe haemophilia A. BMJ 1979; 1 (6161): 469-470
    CrossrefPubMedGoogle Scholar
  • 4 Hoots WK. Pathogenesis of hemophilic arthropathy. Semin Hematol 2006; 43 (01) (Suppl. 01) S18-S22
    PubMedGoogle Scholar
  • 5 Oldenburg J, Zimmermann R, Katsarou O. , et al; Cross-sectional MRI study investigators. Controlled, cross-sectional MRI evaluation of joint status in severe haemophilia A patients treated with prophylaxis vs. on demand. Haemophilia 2015; 21 (02) 171-179
    CrossrefPubMedGoogle Scholar
  • 6 Morris CJ, Blake DR, Wainwright AC, Steven MM. Relationship between iron deposits and tissue damage in the synovium: an ultrastructural study. Ann Rheum Dis 1986; 45 (01) 21-26
    CrossrefPubMedGoogle Scholar
  • 7 Roosendaal G, Vianen ME, Wenting MJ. , et al. Iron deposits and catabolic properties of synovial tissue from patients with haemophilia. J Bone Joint Surg Br 1998; 80 (03) 540-545
    CrossrefPubMedGoogle Scholar
  • 8 Sen D, Chapla A, Walter N, Daniel V, Srivastava A, Jayandharan GR. Nuclear factor (NF)-κB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia. J Thromb Haemost 2013; 11 (02) 293-306
    CrossrefPubMedGoogle Scholar
  • 9 Nieuwenhuizen L, Schutgens RE, Coeleveld K. , et al. Hemarthrosis in hemophilic mice results in alterations in M1–M2 monocyte/macrophage polarization. Thromb Res 2014; 133 (03) 390-395
    CrossrefPubMedGoogle Scholar
  • 10 Hoppstädter J, Seif M, Dembek A. , et al. M2 polarization enhances silica nanoparticle uptake by macrophages. Front Pharmacol 2015; 6: 55
    PubMedGoogle Scholar
  • 11 Steinbrecher KA, Horowitz NA, Blevins EA. , et al. Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen. Cancer Res 2010; 70 (07) 2634-2643
    CrossrefPubMedGoogle Scholar
  • 12 Kopec AK, Abrahams SR, Thornton S. , et al. Thrombin promotes diet-induced obesity through fibrin-driven inflammation. J Clin Invest 2017; 127 (08) 3152-3166
    CrossrefPubMedGoogle Scholar
  • 13 von Brühl ML, Stark K, Steinhart A. , et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
    CrossrefPubMedGoogle Scholar
  • 14 Rathnakumar K, Savant S, Giri H. , et al. Angiopoietin-2 mediates thrombin-induced monocyte adhesion and endothelial permeability. J Thromb Haemost 2016; 14 (08) 1655-1667
    CrossrefPubMedGoogle Scholar
  • 15 Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296 (5574): 1880-1882
    CrossrefPubMedGoogle Scholar
  • 16 Kopec AK, Joshi N, Cline-Fedewa H. , et al. Fibrin(ogen) drives repair after acetaminophen-induced liver injury via leukocyte αMβ2 integrin-dependent upregulation of Mmp12. J Hepatol 2017; 66 (04) 787-797
    CrossrefPubMedGoogle Scholar
  • 17 Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol 2011; 11 (11) 762-774
    CrossrefPubMedGoogle Scholar
  • 18 Park H, Ishihara D, Cox D. Regulation of tyrosine phosphorylation in macrophage phagocytosis and chemotaxis. Arch Biochem Biophys 2011; 510 (02) 101-111
    CrossrefPubMedGoogle Scholar
  • 19 McWhorter FY, Wang T, Nguyen P, Chung T, Liu WF. Modulation of macrophage phenotype by cell shape. Proc Natl Acad Sci U S A 2013; 110 (43) 17253-17258
    CrossrefPubMedGoogle Scholar
  • 20 Masters TA, Pontes B, Viasnoff V, Li Y, Gauthier NC. Plasma membrane tension orchestrates membrane trafficking, cytoskeletal remodeling, and biochemical signaling during phagocytosis. Proc Natl Acad Sci U S A 2013; 110 (29) 11875-11880
    CrossrefPubMedGoogle Scholar
  • 21 Grunfeld C, Zhao C, Fuller J. , et al. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest 1996; 97 (09) 2152-2157
    CrossrefPubMedGoogle Scholar
  • 22 Maffei M, Halaas J, Ravussin E. , et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1 (11) 1155-1161
    CrossrefPubMedGoogle Scholar
  • 23 Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8 (12) 958-969
    CrossrefPubMedGoogle Scholar
  • 24 Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998; 101 (04) 890-898
    CrossrefPubMedGoogle Scholar
  • 25 Mirza R, DiPietro LA, Koh TJ. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol 2009; 175 (06) 2454-2462
    CrossrefPubMedGoogle Scholar
  • 26 Hart PH, Vitti GF, Burgess DR, Whitty GA, Piccoli DS, Hamilton JA. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2. Proc Natl Acad Sci U S A 1989; 86 (10) 3803-3807
    CrossrefPubMedGoogle Scholar
  • 27 Bogdan C, Paik J, Vodovotz Y, Nathan C. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem 1992; 267 (32) 23301-23308
    CrossrefPubMedGoogle Scholar
  • 28 Fleetwood AJ, Lawrence T, Hamilton JA, Cook AD. Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol 2007; 178 (08) 5245-5252
    CrossrefPubMedGoogle Scholar
  • 29 Forget MA, Voorhees JL, Cole SL. , et al. Macrophage colony-stimulating factor augments Tie2-expressing monocyte differentiation, angiogenic function, and recruitment in a mouse model of breast cancer. PLoS One 2014; 9 (06) e98623
    CrossrefPubMedGoogle Scholar
  • 30 Kress H, Stelzer EH, Holzer D, Buss F, Griffiths G, Rohrbach A. Filopodia act as phagocytic tentacles and pull with discrete steps and a load-dependent velocity. Proc Natl Acad Sci U S A 2007; 104 (28) 11633-11638
    CrossrefPubMedGoogle Scholar
  • 31 Buechler C, Ritter M, Orsó E, Langmann T, Klucken J, Schmitz G. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 2000; 67 (01) 97-103
    CrossrefPubMedGoogle Scholar
  • 32 Lacey DC, Achuthan A, Fleetwood AJ. , et al. Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models. J Immunol 2012; 188 (11) 5752-5765
    CrossrefPubMedGoogle Scholar
  • 33 Neu C, Sedlag A, Bayer C. , et al. CD14-dependent monocyte isolation enhances phagocytosis of listeria monocytogenes by proinflammatory, GM-CSF-derived macrophages. PLoS One 2013; 8 (06) e66898
    CrossrefPubMedGoogle Scholar
  • 34 Boocock CA, Jones GE, Stanley ER, Pollard JW. Colony-stimulating factor-1 induces rapid behavioural responses in the mouse macrophage cell line, BAC1.2F5. J Cell Sci 1989; 93 (Pt 3): 447-456
    PubMedGoogle Scholar
  • 35 Shi C, Zhang X, Chen Z. , et al. Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1. J Clin Invest 2004; 114 (03) 408-418
    CrossrefPubMedGoogle Scholar
  • 36 Joshi S, Singh AR, Zulcic M. , et al. Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo. PLoS One 2014; 9 (04) e95893
    CrossrefPubMedGoogle Scholar
  • 37 Knowles LM, Malik G, Pilch J. Plasma fibronectin promotes tumor cell survival and invasion through regulation of Tie2. J Cancer 2013; 4 (05) 383-390
    CrossrefPubMedGoogle Scholar
  • 38 Tippett E, Cheng WJ, Westhorpe C. , et al. Differential expression of CD163 on monocyte subsets in healthy and HIV-1 infected individuals. PLoS One 2011; 6 (05) e19968
    CrossrefPubMedGoogle Scholar
  • 39 Goren I, Allmann N, Yogev N. , et al. A transgenic mouse model of inducible macrophage depletion: effects of diphtheria toxin-driven lysozyme M-specific cell lineage ablation on wound inflammatory, angiogenic, and contractive processes. Am J Pathol 2009; 175 (01) 132-147
    CrossrefPubMedGoogle Scholar
  • 40 Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 2013; 229 (02) 176-185
    CrossrefPubMedGoogle Scholar
  • 41 Flick MJ, LaJeunesse CM, Talmage KE. , et al. Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif. J Clin Invest 2007; 117 (11) 3224-3235
    CrossrefPubMedGoogle Scholar
  • 42 Laouar A, Collart FR, Chubb CB, Xie B, Huberman E. Interaction between alpha 5 beta 1 integrin and secreted fibronectin is involved in macrophage differentiation of human HL-60 myeloid leukemia cells. J Immunol 1999; 162 (01) 407-414
    PubMedGoogle Scholar
  • 43 Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395 (6704): 763-770
    CrossrefPubMedGoogle Scholar
  • 44 Lagrand WK, Visser CA, Hermens WT. , et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon?. Circulation 1999; 100 (01) 96-102
    CrossrefPubMedGoogle Scholar
  • 45 Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999; 282 (22) 2131-2135
    CrossrefPubMedGoogle Scholar
  • 46 Cardoso CR, Leite NC, Salles GF. Prognostic importance of C-reactive protein in high cardiovascular risk patients with type 2 diabetes mellitus: the Rio de Janeiro Type 2 Diabetes Cohort Study. J Am Heart Assoc 2016; 5 (11) e004554
    PubMedGoogle Scholar
  • 47 Sood SL, Cheng D, Ragni M. , et al. A cross-sectional analysis of cardiovascular disease in the hemophilia population. Blood Adv 2018; 2 (11) 1325-1333
    CrossrefPubMedGoogle Scholar