title: Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression.
abstract: Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe(-/-) mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8 weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6C(high) monocytes and macrophages. SYK inhibition limited Ly6C(high) monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe(-/-) mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression.
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lindau
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Härdtner
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Sonja P
authors.initials: SP
authors.lastname: Hergeth
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.|Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Kelly Daryll
authors.initials: KD
authors.lastname: Blanz
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Dufner
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Hoppe
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Nathaly
authors.initials: N
authors.lastname: Anto-Michel
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kornemann
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Jiadai
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Louisa M S
authors.initials: LM
authors.lastname: Gerhardt
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Heidt
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Willecke
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Serjosha
authors.initials: S
authors.lastname: Geis
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Stachon
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wolf
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.affiliation: Peter Munk Cardiac Centre, Toronto, ON, Canada.
authors.forename: Clinton S
authors.initials: CS
authors.lastname: Robbins
authors.affiliation: AstraZeneca R&D, Molndal, Gothenburg, Sweden.
authors.forename: William
authors.initials: W
authors.lastname: McPheat
authors.affiliation: AstraZeneca R&D, Alderley Park, Macclesfield, UK.
authors.forename: Shaun
authors.initials: S
authors.lastname: Hawley
authors.affiliation: AstraZeneca R&D, Alderley Park, Macclesfield, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Braddock
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gilsbach
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: von zur Mühlen
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. andreas.zirlik@universitaets-herzzentrum.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
authors.affiliation: Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. ingo.hilgendorf@universitaets-herzzentrum.de.
authors.forename: Ingo
authors.initials: I
authors.lastname: Hilgendorf
mesh_terms: D000631:Aminopyridines; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009000:Monocytes / Q000187:drug effects*; D009025:Morpholines; D038042:Myelopoiesis / Q000187:drug effects*; D010078:Oxazines / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines; D011897:Random Allocation; D000072377:Syk Kinase
chemical_list: D000631:Aminopyridines; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C523665:fostamatinib
keywords: Atherosclerosis; Egress; Macrophages; Monocytes; Progenitors; Proliferation; SYK