CD16+ monocytes in atherogenesis and uremia
Monocytes play a central role in the initiation and progression of atherosclerosis. They are considered to be key drivers of chronic microinflammation and vascular disease encountered in the Cardio-Renal Syndrome (Ronco JACC 2008). Monocytes display significant functional and phenotypic heterogeneity. Flow cytometry allows to distinguish between CD14++CD16- and CD16-positive monocytes; the latter subset can further be divided into CD14++CD16+ and CD14+CD16++ monocytes according to the international consensus (Ziegler-Heitbrock Blood 2010). The three monocyte subsets can be also differentiated by a distinct genetic endowment, that we have recently deciphered via Next Generation Sequencing after isolation of the three respective monocyte subpopulations (Zawada Blood 2011, Figure 1).
Figure 1: Isolated monocyte subsets.
CD16-positive monocytes are thought to represent proatheroscleoric monocytes, as suggested by genetic and functional analyses (e.g. via pronounced secretion of proinflammatory cytokines, adhesion to endothelial cells and the potential to perpetuate vascular injury via the attraction of further immune cells to the vessel wall).
Compared to individuals with intact renal function patients with chronic kidney disease (CKD) display a shift in monocyte subsets towards CD16-positive monocytes (Figure 2). We observed this in CKD patients not yet on dialysis as well as in haemodialysis patients (Rogacev EHJ 2011) (Figure 3).
Figure 2: Monocyte subsets in a dialysis patient (left panel) and an age- and gender-matched control subject (right panel; representative example).
Figure 3: Intermediate CD14++CD16+ monocyte counts in matched pairs (subjects with intact renal function, patients with stage 4-5 CKD not yet on dialysis and haemodialysis patients).
In prospective cohort studies, we identified CD14++CD16+ monocytes as independent predictors of cardiovascular events in haemodialysis patients (Heine KI 2008), non-dialysis CKD patients (Rogacev EHJ 2011) and in patients referred for elective coronary angiography (Rogacev JACC 2012, Figure 4).
Figure 4: Event-free survival in patients referred for elective coronary angiography after stratification for CD14++CD16+ monocyte counts.
In addition, we are presently investigating the role of monocyte subpopulation activation status non-dialysis CKD patients in our CARE FOR HOMe cohort. We are aiming to delineate differences of monocyte subpopulations on the cellular and molecular level in order to understand why patients suffering from chronic kidney disease have increased numbers of CD16-positive monocytes.
Ultimately, our studies will hopefully provide a better understanding of human monocyte biology allowing the development of immunomodulatory strategies for the treatment of vascular disease in Cardio-Renal Syndrome.
Publications
Selection of publications concerning the research focus since 2008
Zawada AM, Schneider JS, Michel AI, Rogacev KS, Hummel B, Krezdorn N, Muller S, Rotter B, Winter P, Obeid R, Geisel J, Fliser D, Heine GH.
DNA methylation profiling reveals differences in the three human monocyte subsets and identifies uremia to induce DNA methylation changes during differentiation.
Epigenetics. 2016;11(4):259-272. Impact factor: 4.8 Abstract
Fell LH, Seiler-Mussler S, Sellier AB, Rotter B, Winter P, Sester M, Fliser D, Heine GH, Zawada AM.
Impact of individual intravenous iron preparations on the differentiation of monocytes towards macrophages and dendritic cells.
Nephrol Dial Transplant. 2016. Impact factor: 4.1 Abstract
Hofer TP, Zawada AM, Frankenberger M, Skokann K, Satzl AA, Gesierich W, Schuberth M, Levin J, Danek A, Rotter B, Heine GH, Ziegler-Heitbrock L.
Characterization of subsets of the CD16-positive monocytes: impact of granulomatous inflammation and M-CSF-receptor mutation.
Blood. 2015. Impact Punkte: 10,5 Abstract
Zawada AM1, Fell LH1, Untersteller K, Seiler S, Rogacev KS, Fliser D, Ziegler-Heitbrock L, Heine GH.
Comparison of two different strategies for human monocyte subsets gating within the large-scale prospective CARE FOR HOMe Study.
Cytometry A 2015 Jun 9. Impact factor: 3.1 Abstract
Rogacev KS1, Zawada AM1, Hundsdorfer J, Achenbach M, Held G, Fliser D, Heine GH.
Immunosuppression and monocyte subsets.
Nephrol Dial Transplant 2015 Jan;30(1):143-53. Impact factor: 3.5 Abstract
Rogacev KS, Zawada AM, Emrich I, Seiler S, Bohm M, Fliser D, Woollard KJ, Heine GH.
Lower Apo A-I and Lower HDL-C Levels Are Associated With Higher Intermediate CD14++CD16+ Monocyte Counts That Predict Cardiovascular Events in CKD.
Arterioscler Thromb Vasc Biol 2014 Jul 24. Impact factor: 6.3 Abstract
Fell LH, Zawada AM, Rogacev KS, Seiler S, Fliser D, Heine GH.
Distinct immunologic effects of different intravenous iron preparations on monocytes.
Nephrol Dial Transplant 2014 Feb 11. Impact factor: 3.4 Abstract
Seibert E, Heine GH, Ulrich C, Seiler S, Kohler H, Girndt M.
Influence of Cholecalciferol Supplementation in Hemodialysis Patients on Monocyte Subsets: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Nephron Clin Pract 2013 Aug 29;123(3-4):209-19. Impact factor: 1.7 Abstract
Zawada AM, Rogacev KS, Hummel B, Grün OS, Friedrich A, Rotter B, Winter P, Geisel J, Fliser D, Heine GH.
SuperTAG Methylation-Specific Digital Karyotyping (SMSDK) Reveals Uremia Induced Epigenetic Dysregulation of Atherosclerosis-Related Genes.
Circ Cardiovasc Genet 2012 Dec 1;5(6):611-20. Impact factor: 6.1 Abstract
Rogacev KS, Cremers B, Zawada AM, Seiler S, Binder N, Ege P, Grosse-Dunker G, Heisel I, Hornof F, Jeken J, Rebling NM, Ulrich C, Scheller B, Bohm M, Fliser D, Heine GH.
CD14++CD16+ Monocytes Independently Predict Cardiovascular Events: A Cohort Study of 951 Patients Referred for Elective Coronary Angiography.
J Am Coll Cardiol 2012 Oct 16;60(16):1512-20. Impact factor: 14.2 Abstract
Heine GH, Ortiz A, Massy ZA, Lindholm B, Wiecek A, Martinez-Castelao A, Covic A, Goldsmith D, Suleymanlar G, London GM, Parati G, Sicari R, Zoccali C, Fliser D.
Monocyte subpopulations and cardiovascular risk in chronic kidney disease.
Nat Rev Nephrol 2012;8(6):362-9. Impact factor: 7.1 Abstract
Zawada AM, Rogacev KS, Rotter B, Winter P, Marell RR, Fliser D, Heine GH.
SuperSAGE evidence for CD14++CD16+ monocytes as a third monocyte subset.
Blood 2011 Sep 22;118(12):e50-61. Impact factor: 10.6. Abstract
Ulrich C, Seibert E, Heine GH, Fliser D, Girndt M.
Monocyte Angiotensin Converting Enzyme Expression May Be Associated with Atherosclerosis Rather than Arteriosclerosis in Hemodialysis Patients.
Clin J Am Soc Nephrol 2011 Mar;6(3):505-11. Impact factor: 4.8. Abstract
Rogacev KS, Seiler S, Zawada AM, Reichart B, Herath E, Roth D, Ulrich C, Fliser D, Heine GH.
CD14++CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease.
Eur Heart J 2011 Jan;32(1):84-92. Impact factor: 9.8. Abstract
Ulrich C, Heine GH, Seibert E, Fliser D, Girndt M.
Circulating monocyte subpopulations with high expression of angiotensin-converting enzyme predict mortality in patients with end-stage renal disease.
Nephrol Dial Transplant 2010 Jul;25(7):2265-72. Impact factor: 3.3. Abstract
Rogacev KS, Heine GH.
Human monocyte heterogeneity-a nephrological perspective.
Nephrol Ther 2010 Jul;6(4):219-25. Impact factor: 0.4. Abstract
Rogacev KS, Ulrich C, Blomer L, Hornof F, Oster K, Ziegelin M, Cremers B, Grenner Y, Geisel J, Schlitt A, Kohler H, Fliser D, Girndt M, Heine GH.
Monocyte heterogeneity in obesity and subclinical atherosclerosis.
Eur Heart J 2010 Feb;31(3):369-76. Impact factor: 9.8. Abstract
Rogacev KS, Ziegelin M, Ulrich C, Seiler S, Girndt M, Fliser D, Heine GH.
Haemodialysis-induced transient CD16+ monocytopenia and cardiovascular outcome.
Nephrol Dial Transplant 2009 Nov;24(11):3480-6. Impact factor: 3.6. Abstract
Heine GH, Ulrich C, Seibert E, Seiler S, Marell J, Reichart B, Krause M, Schlitt A, Köhler H, Girndt M.
CD14++CD16+ Monocyte Counts, but Not Total Monocyte Counts, Predict Cardiovascular Events in Dialysis Patients.
Kidney Int 2008 Mar;73(5):622-9. Impact factor: 4.8. Abstract
Ulrich C, Heine GH, Gerhart MK, Köhler H, Girndt M.
Proinflammatory CD14+CD16+ monocytes are associated with subclinical atherosclerosis in renal transplant patients.
Am J Transplant 2008 Jan;8(1):103-10. Impact factor: 6.8. Abstract
