2. Academic Validation
  3. Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease

Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease

  • Circulation. 2021 Sep 14;144(11):893-908. doi: 10.1161/CIRCULATIONAHA.121.053547.
Stefan J Schunk 1,  Sarah Triem 1 2,  David Schmit 1,  Stephen Zewinger 1,  Tamim Sarakpi 1,  Ellen Becker 1 2,  Gregor Hütter 1 2,  Selina Wrublewsky 3,  Fabienne Küting 1 2,  Mathias Hohl 4,  Dalia Alansary 5,  Leticia Prates Roma 5,  Peter Lipp 6,  Julia Möllmann 7,  Michael Lehrke 7,  Matthias W Laschke 3,  Michael D Menger 3,  Rafael Kramann 8 9,  Peter Boor 10,  Willi Jahnen-Dechent 11,  Winfried März 12 13 14,  Michael Böhm 4,  Ulrich Laufs 15,  Barbara A Niemeyer 5,  Danilo Fliser 1,  Emmanuel Ampofo  # 3,  Thimoteus Speer  # 1 2
Affiliations

Affiliations

  • 1 Department of Internal Medicine IV, Nephrology and Hypertension (S.J.S., S.T., D.S., S.Z., T. Sarakpi, E.B., G.H., F.K., D.F., T. Speer), Saarland University, Homburg/Saar, Germany.
  • 2 Translational Cardiorenal Medicine (S.T., E.B., G.H., F.K., T. Speer), Saarland University, Homburg/Saar, Germany.
  • 3 Institute of Clinical and Experimental Surgery (S.W., M.W.L., M.D.M., E.A.), Saarland University, Homburg/Saar, Germany.
  • 4 Department of Internal Medicine III, Cardiology, Angiology, and Intensity Care Medicine (M.H., M.B.), Saarland University, Homburg/Saar, Germany.
  • 5 Institute of Biophysics, Center of Integrative Physiology and Molecular Medicine (CIPMM) (D.A., L.P.R., B.A.N.), Saarland University, Homburg/Saar, Germany.
  • 6 Institute of Cell Biology (P.L.), Saarland University, Homburg/Saar, Germany.
  • 7 Department of Cardiology (J.M., M.L.), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital, Germany.
  • 8 Department of Nephrology (R.K.), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital, Germany.
  • 9 Institute of Experimental Medicine and Systems Biology (R.K.), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital, Germany.
  • 10 Institute of Pathology (P.B.), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital, Germany.
  • 11 Biointerface Laboratory (W.J.-D.), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital, Germany.
  • 12 Vth Department of Medicine, University Heidelberg, Mannheim Medical Faculty, Mannheim, Germany (W.M.).
  • 13 Clinical Institute of Medical and Laboratory Diagnostics, Medical University Graz, Austria (W.M.).
  • 14 Synlab Academy, Synlab Holding, Mannheim, Germany (W.M.).
  • 15 Department of Cardiology, University Hospital Leipzig, Germany (U.L.).
  • # Contributed equally.
PMID: 34192892 DOI: 10.1161/CIRCULATIONAHA.121.053547
Abstract

Background: Cardiovascular diseases and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin interleukin-1α (IL-1α) is expressed in a variety of cell types promoting (sterile) systemic inflammation. The aim of the present study was to examine the role of IL-1α in mediating inflammation in the setting of acute myocardial infarction (AMI) and CKD.

Methods: We assessed the expression of IL-1α on the surface of monocytes from patients with AMI and patients with CKD and determined its association with atherosclerotic Cardiovascular Disease events during follow-up in an explorative clinical study. Furthermore, we assessed the inflammatory effects of IL-1α in several organ injury models in Il1a-/- and Il1b-/- mice and investigated the underlying mechanisms in vitro in monocytes and endothelial cells.

Results: IL-1α is strongly expressed on the surface of monocytes from patients with AMI and CKD compared with healthy controls. Higher IL-1α surface expression on monocytes from patients with AMI and CKD was associated with a higher risk for atherosclerotic Cardiovascular Disease events, which underlines the clinical relevance of IL-1α. In mice, IL-1α, but not IL-1β, mediates leukocyte-endothelial adhesion as determined by intravital microscopy. IL-1α promotes accumulation of macrophages and neutrophils in inflamed tissue in vivo. Furthermore, IL-1α on monocytes stimulates their homing at sites of vascular injury. A variety of stimuli such as free fatty acids or oxalate crystals induce IL-1α surface expression and release by monocytes, which then mediates their adhesion to the endothelium via IL-1 receptor-1. IL-1α also promotes expression of the VCAM-1 (vascular cell adhesion molecule-1) on endothelial cells, thereby fostering the adhesion of circulating leukocytes. IL-1α induces inflammatory injury after experimental AMI, and abrogation of IL-1α prevents the development of CKD in oxalate or adenine-fed mice.

Conclusions: IL-1α represents a key mediator of leukocyte-endothelial adhesion and inflammation in AMI and CKD. Inhibition of IL-1α may serve as a novel anti-inflammatory treatment strategy.

Keywords

chronic kidney disease; inflammation; interleukin-1α; leukocyte adhesion; myocardial infarction.

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